Daptomycin resistance in Enterococcus faecalis prosthetic valve endocarditis

Sir, Daptomycin resistance is unusual. We report a case of clinical and bacteriological failure in a patient with Enterococcus faecalis endocarditis treated with daptomycin and review available data on daptomycin resistance. A 53-year-old male was hospitalized for native mitral valve endocarditis due to methicillin-susceptible Staphylococcus aureus. Treatments with nafcillin and then vancomycin were discontinued due to a severe rash with both agents. Daptomycin was initiated followed by mitral valve replacement. The patient had a complicated, 2 month hospital course during which he developed a stage IV decubitus ulcer colonized with vancomycin-resistant E. faecalis. He completed 8 weeks of daptomycin at 6 mg/kg/day. One month after discharge, the patient was diagnosed with prosthetic mitral valve endocarditis caused by vancomycin-resistant E. faecalis. A transoesophageal echocardiogram showed multiple vegetations on the posterior leaflet of the mitral valve. Owing to penicillin allergy, treatment with daptomycin was initiated. Blood cultures on day 1 grew three different strains of E. faecalis, including a vancomycin-resistant daptomycin-susceptible E. faecalis (MIC >512 and 4 mg/L, respectively), a vancomycin-susceptible daptomycin-non-susceptible E. faecalis (MIC 2 and >8 mg/L, respectively), and a vancomycin-resistant daptomycin-non-susceptible E. faecalis (MIC >512 and >8 mg/L, respectively). Susceptibility testing was performed using MicroScan broth microdilution (Dade Behring Inc., West Sacramento, CA, USA). Daptomycin MICs were performed using Etest strips (AB Biodisk North America Inc., Piscataway, NJ, USA) on Mueller–Hinton plates and were confirmed at the CDC. Daptomycin susceptibility methods were supplemented with additional calcium, as recommended by the CLSI.1 Blood cultures on hospital days 2 and 4 again grew vancomycin-resistant, daptomycin-non-susceptible E. faecalis. Penicillin desensitization was attempted unsuccessfully. Linezolid was started on hospital day 7 and blood cultures cleared on day 9. Because he had heparin-induced thrombocytopenia, repeat valve replacement presented a high risk of stroke while on cardiac bypass. The patient therefore elected medical management. He was discharged on hospital day 16 on oral linezolid therapy for palliation. Ten days after discharge, bacteraemia returned. He elected hospice care and expired shortly thereafter. Antibacterial agents with activity against emerging multidrug-resistant Gram-positive pathogens are limited. Daptomycin is a novel cyclic lipopeptide that binds the cell membrane in a calcium-dependent fashion causing depolarization and release of intracellular ions with arrest in macromolecular synthesis and cell death.2 It is bactericidal against both susceptible and resistant Gram-positive organisms and has a low toxicity profile.2 However, it is not approved for use in vancomycin-resistant Enterococcus infections. Little is known about the potential emergence of daptomycin resistance among these species and there are no defined MIC breakpoints for a resistant category for Enterococcus according to the USA-FDA and CLSI. Case reports of clinical failures with daptomycin in S. aureus infections emerged shortly after approval.3 However, resistance among Enterococcus species has been reported in only seven published cases (Table 1).4–10 Currently, there are no studies on mechanisms of daptomycin resistance in enterococcal species. For S. aureus, changes in membrane structure and function correlate with in vivo development of daptomycin non-susceptibility,11,12 and mutations in proteins involved in cell permeability have been implicated in daptomycin MIC increases.13 Daptomycin, a large molecule, may get trapped in the cell wall, unable to bind its target in the cell membrane. Supporting this hypothesis, elevated daptomycin MICs have been found to correlate with decreased susceptibility to vancomycin in >90% of the S. aureus isolates,14 and the level of resistance for both drugs has been found to correlate positively with cell wall thickness in glycopeptide-intermediate S. aureus isolates.15 Daptomycin non-susceptible Enterococcus species isolates: case reports ESRD, end-stage renal disease; AML, acute myeloid leukaemia; DM, diabetes mellitus; HL, Hodgkin's lymphoma; CKD, chronic kidney disease; CHF, congestive heart failure; VR, vancomycin-resistant; PCN, penicillin; ref, reference; NR, not reported. Daptomycin non-susceptible Enterococcus species isolates: case reports ESRD, end-stage renal disease; AML, acute myeloid leukaemia; DM, diabetes mellitus; HL, Hodgkin's lymphoma; CKD, chronic kidney disease; CHF, congestive heart failure; VR, vancomycin-resistant; PCN, penicillin; ref, reference; NR, not reported. More recently, emergence of daptomycin heteroresistance was demonstrated for a vancomycin-heteroresistant E. faecium after exposure to vancomycin, suggesting the same underlying resistance mechanism.16 During therapy with daptomycin for S. aureus bacteraemia and endocarditis, 16% of the patients failed with a persistent or relapsing infection with increasing isolate MICs. Most of these failures were in deep-seated infections for which a necessary surgical intervention was not performed.17 In the case of Enterococcus, either a chronic indwelling line or persistent focus of infection was reported for all but two of the seven reported cases of daptomycin clinical treatment failures, and non-susceptibility developed on treatment after an average of 19 days.4–10 The mechanisms of non-susceptibility to daptomycin are thus diverse and not completely understood. Increasing MICs in the setting of pre-exposure to either vancomycin or daptomycin and/or evidence of a persistent focus of infection seem to be a frequent occurrence for clinical failures among both S. aureus and Enterococcus species. Despite lack of experimental data, it is plausible that the mechanisms that explain enterococcal non-susceptibility parallel those for S. aureus. The use of daptomycin in patients with prior prolonged vancomycin or daptomycin therapy, or with a focus of infection that cannot be removed, should be undertaken with caution, as clinical failure can occur. No specific funding was received for this study. None to declare.