Emergence of Resistance to Daptomycin during Treatment of Vancomycin-Resistant Enterococcus faecalis Infection

SIR—Daptomycin is a recently approved antibiotic intended for the treatment of complicated soft-tissue infection. It has in vitro bactericidal activity against gram-positive pathogens [1–5]. We report the case of a 64-year-old woman with cryptogenic cirrhosis who had recently begun hemodialysis with a tunneled intravenous catheter. In May 2004, she presented with hypotension to a community hospital in Indiana and was found to have high-grade bacteremia due to ampicillin-susceptible, vancomycin-resistant Enterococcus faecalis (isolates 1 and 2 in figure 1). Because of her history of penicillin allergy, she was treated with linezolid, and the hemodialysis catheter was removed. Results of culture of the catheter's tip were positive for E. faecalis. Because the patient developed thrombocytopenia, treatment with linezolid was discontinued. The patient was later discharged from the hospital with a prescribed regimen of oral ciprofloxacin. A few days later, she was rehospitalized with fever and blood culture results that were positive for E. faecalis (isolate 3 in figure 1). Treatment with daptomycin and amikacin was initiated in June 2004. The patient's hemodialysis catheter was again removed. Findings of a transesophageal echocardiogram were negative for vegetations. Results of additional blood cultures were negative for E. faecalis, and a new hemodialysis catheter was inserted. The patient was discharged from the hospital with a prescribed regimen of daptomycin 400 mg q48h in addition to amikacin during hemodialysis. PFGE of SmaI-digested chromosomal DNA. Lane 1, isolate 1; lane 2, isolate 2; lane 3, isolate 3; lane 4, isolate 4; lane 5, λ marker. Approximately 2 weeks after the patient was discharged from the hospital, she was rehospitalized with fever and blood culture results that were positive for E. faecalis (isolate 4 in figure 1). Treatment with daptomycin and amikacin was stopped, and treatment with linezolid was restarted. The patient was transferred to a nearby university hospital for ampicillin desensitization. She remained bacteremic, despite receipt of high doses of intravenous ampicillin, and later died. No autopsy was performed. Four E. faecalis isolates were tested: 2 obtained during the initial episode of bacteremia (isolates 1 and 2 in figure 1), 1 isolate obtained just prior to the start of treatment with daptomycin (isolate 3 in figure 1), and 1 isolate obtained during the patient's relapse while she was receiving treatment with daptomycin (isolate 4 in figure 1). Genomic DNA was digested with SmaI, as has been described elsewhere by Matushek et al. [6]. We determined MICs by broth microdilution using Mueller-Hinton broth supplemented with 50 mg/L of Ca2+, according to the guidelines of the NCCLS [7, 8]. Daptomycin was obtained from Cubist Pharmaceuticals. PFGE showed indistinguishable patterns between all 4 isolates of E. faecalis, as seen in figure 1. Isolates 1, 2, and 3 had daptomycin MICs of 1µg/mL, and isolate 4 had an increased daptomycin MIC of 16 µg/mL (nonsusceptibility to daptomycin is defined as an MIC of ⩾8 µg/mL). Susceptibilities of isolates 1 and 4 to vancomycin, linezolid, and synercid were unchanged (data not shown). Daptomycin is considered one of the few therapeutic options for the management of vancomycin-resistant E. faecalis infection [9]. The spontaneous emergence of daptomycin-resistance in vitro has been unsuccessful [10], and, thus far, no cases of resistance in humans have been published. We believe this to be the first case E. faecalis infection reported in which resistance to daptomycin developed while the patient was receiving therapy. Further studies will be done to determine the molecular mechanism of resistance. We thank Irene Dusich for providing the isolates, and we thank Drs. Carolina Ocampo and Richard Yu for providing care for the patient. Financial support. This letter was partially funded by a grant from Cubist pharmaceuticals. Potential conflicts of interest. L.S.M.P. serves as a consultant for Cubist pharmaceuticals. J.P.Q. serves as a consultant and speaker for Cubist pharmaceuticals. K.L.: no conflict.