When Daptomycin Fails: Practical Approaches to Resistant Enterococcus faecium

A liver transplant recipient who requires reoperation for biliary leak develops vancomycin- resistant Enterococcus faecium (VREfm) bacteremia and is treated with a prolonged course of high-dose daptomycin, abdominal washout, and biliary stent placement.

Three weeks after stopping antibiotics, he presents with sepsis secondary to recurrent VREfm bacteremia that is now resistant to daptomycin (sensitive to linezolid, tigecycline, and eravacycline). What are the next steps?

Daptomycin-resistant E faecium (DREfm) is an emerging threat, particularly among transplant recipients and patients with hematologic malignancies. As daptomycin remains the first-line treatment for ampicillin- and vancomycin-resistant E faecium, the bacteria’s increasing resistance poses significant therapeutic challenges.

Background and Epidemiology

The E faecium that was initially isolated in this case was resistant to ampicillin and vancomycin. Resistance to ampicillin and vancomycin is common, occurring in over 90% and 83% of E faecium, respectively. ^1,2 Daptomycin, the antibiotic used in this case, is widely used for serious VREfm infections because of its bactericidal activity and favorable adverse effect profile, despite the lack of FDA approval for this indication. Higher doses of 10 mg/kg or greater are associated with reduced mortality compared with lower doses.³ The development of daptomycin resistance that occurred in this case is an emerging challenge, particularly in similar high-risk patients, with limited alternative options and increased mortality.⁴

The overall prevalence of DREfm is low; however, up to 35% of VREfm infections in patients with hematologic malignancies or liver transplant recipients are daptomycin resistant.^4-7 This patient had prior daptomycin use, which increases the risk for resistance, but it can also occur de novo without prior exposure or in combination with sensitive phenotypes.⁷

Mechanisms of DREfm

Daptomycin resistance may emerge during therapy, especially with suboptimal dosing, high bacterial burdens, or inadequate source control.^6,8 Resistance results from mutations affecting cell membrane charge and phospholipid metabolism, which reduce daptomycin binding.^9,10 Resistance to other agents (eg, vancomycin or linezolid) may be observed due to the plasmid-mediated transfer of resistance.

Risk Factors for DREfm

Prior daptomycin exposure was one of the patient’s key risks for DREfm infection, associated with up to 30-fold higher odds of resistance.⁴ His additional risk factors for DREfm included liver transplantation, reoperation, biliary leak, and prolonged hospital stay. Deep-seated infections without adequate source control and biofilms predispose to the emergence of resistance. Populations disproportionately affected include solid organ transplant recipients (particularly liver transplant recipients), patients with malignancies or bone marrow transplantation, and critically ill patients.¹¹

These groups are likely vulnerable due to intensive broad-spectrum antimicrobial exposure, mucosal barrier disruption, and use of indwelling devices. Among solid organ transplant recipients, liver transplant recipients are especially susceptible, likely related to intestinal and biliary manipulation during surgery and gut dysbiosis associated with end-stage liver disease.^12,13 In this population, surgical complications requiring reintervention, particularly anastomotic leaks, are strongly associated with DREfm infections.^4,14

Diagnostic Considerations

Rising minimum inhibitory concentrations (MICs), clinical deterioration, or persistent bacteremia while on daptomycin should prompt repeat sensitivity testing.¹⁵ The MIC should be confirmed using alternative methods when daptomycin resistance is suspected. Due to an increased risk for microbiologic failure at daptomycin MIC 3 to 4 μg/mL, the Clinical and Laboratory Standards Institute updated the daptomycin breakpoints in 2019 with MIC less than or equal to 4 μg/mL susceptible-dose dependent and MIC greater than or equal to 8 μg/mL daptomycin resistant.¹⁶ Broth microdilution using calcium-supplemented media is considered the reference method, but variability exists across platforms.^10,17 At our institution, Sensititre testing is performed and reflexed to an Etest if resistance is suspected. Clinical failure is often a more important marker than the MIC value itself.

Clinical Management

Management of DREfm begins with confirming clinical significance and obtaining source control (Figure). In our case, with DREfm isolated on blood culture with signs of sepsis, the clinical significance was clear. However, depending on the site and clinical context, recovery of DREfm may represent colonization rather than a clinically significant infection, which may not require treatment. Early and aggressive interventions for source control are critical for the management of deep-seated DREfm infections. In our case, once the DREfm infection was identified, repeat imaging was performed. That identified a new perihepatic liver abscess, which was subsequently drained, and central lines were removed.

Other interventions include removing infected devices and addressing other undrained sources to cure and prevent further resistance from developing. Early consultation with infectious diseases physicians is recommended. Treatment of DREfm bacteremia is challenging due to the limited treatment options. Linezolid, an oxazolidinone, is the only drug that is approved by the FDA for the treatment of VREfm infections and is considered the drug of choice for DREfm bacteremia.⁴

Clinical use of linezolid is often limited by drug-drug interactions and longterm toxicities, especially myelosuppression, lactic acidosis, peripheral neuropathy, and optic neuropathy.¹⁸ Combination therapy with high-dose daptomycin and β-lactams may be considered for isolates with susceptible-dose dependent MIC (3-4 μg/mL) or partial susceptibility and persistent bacteremia, endocarditis, high bacterial burden, or incomplete source control. β-Lactams enhance daptomycin activity by lowering the cell surface charge and increasing daptomycin binding, but clinical data remain limited.¹⁹ The American Heart Association recommends considering combination therapy if daptomycin is used to treat VREfm infective endocarditis.²⁰ In vitro, ceftaroline, ertapenem, cefepime, and ampicillin all demonstrate synergy with daptomycin, but only ceftaroline provides synergy in daptomycin- resistant strains.^19,21 There are limited clinical data to support alternative regimens, which are considered salvage options for serious DREfm infections and bacteremia (Table). Tigecycline Multidrug-Resistant Infections should not be used as monotherapy for bacteremia due to low serum concentrations and increased mortality risk.²² Eravacycline and omadacycline are newer tetracycline derivatives with potent in vitro activity but limited clinical data.²³

In vitro, omadacycline and tigecycline have similar activity against E faecium, while eravacycline is more potent.10 Emerging data demonstrate eravacycline use is associated with a 50% to 77% cure rate for VRE infections, including daptomycin-resistant, refractory, and endovascular infections.²⁴ Oritavancin is the only lipoglycopeptide with in vitro activity against DREfm, and there are limited data regarding its use.²⁵ Chloramphenicol remains a treatment option in resource-limited settings and for adjunctive therapy.²⁰ Combination therapies are frequently used to treat DREfm infections. For sensitive enterococcal infections, the utility of combination is well established, and combinations of ampicillin, gentamicin, and ceftriaxone are recommended for the treatment of infective endocarditis.²⁰

Evidence regarding combinations of linezolid with gentamicin, rifampin, and doxycycline is contradictory and inconclusive.²⁶ There is limited evidence to support combinations including tigecycline or eravacycline.^24,26 Although combination therapy is not routinely recommended, it should be considered for infections with high bacterial burdens, including endocarditis or persistent bacteremia, especially if source control is not feasible, ideally in consultation with an infectious diseases specialist. Our patient was initially treated with linezolid and piperacillin/tazobactam for a polymicrobial abscess and required over 4 weeks of treatment pending resolution. After 2 weeks, progressive thrombocytopenia prompted his transition to eravacycline.

Stewardship and Prevention

Antimicrobial stewardship interventions to prevent DREfm infections are critical. Avoiding prolonged unnecessary and subtherapeutic daptomycin (< 10mg/kg) may prevent the development of daptomycin resistance.²⁷ Early infectious diseases consultation is imperative to guide management and consider early combination therapy or novel agents, particularly in patients with high bacterial burdens. Institutions that have large high-risk populations, including large transplant and cancer centers, should consider surveillance for rising daptomycin MICs.

Future Directions

Optimal treatment for DREfm remains undefined. Newer tetracycline derivatives and long-acting lipoglycopeptides show promise but lack robust clinical data. The utility of combination therapy remains unclear. Phage therapy is an emerging adjunctive treatment for VRE infections, but it remains experimental.²⁸

References

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