De Novo Daptomycin-Nonsusceptible Enterococcal Infections

Potential emergence of enterococcal daptomycin nonsusceptibility among patients with no prior exposure to daptomycin poses clinical and public health challenges. We found that development of infections with daptomycin-nonsusceptible enterococci in these patients could be associated with sporadic emergence and clonal spread.

complicated concurrent medical conditions, and all but one had undergone surgery in the 3 months before isolation of DNSE (Table 1). For 4 patients, DNSE were isolated on the day of admission. For the remaining 5 patients, the average length of hospitalization before isolation of the fi rst DNSE isolate was 45.4 days ( Table 1).
Use of antimicrobial drugs associated with presence of vancomycin-resistant enterococci, such as recent use of vancomycin, third-generation cephalosporins, or agents with activity against anaerobic bacteria (4), was associated with 5 (55.6%; mean duration 31.6 days, range 5-58 days), 1 (11.1%; duration 12 days), and 6 (66.7%; mean duration 33 days, range 5-65 days) patients, respectively. Recently, we suggested that the interplay between anaerobes and enterococci might have a possible role in the dissemination of daptomycin resistance (5). However, DNSE were also found in 3 (33.3%) patients (patients 3, 4, and 5; Table 1) who had no recent exposure to any antimicrobial agent. In addition, 2 patients (patients 4 and 5; Table 1) had no hospitalization or other health care exposure in the 12-month period before fi rst isolation of DNSE, and DNSE were isolated on the fi rst day of hospitalization, strongly suggesting community acquisition of DNSE.
Further support for a possible community reservoir of DNSE was provided by the identifi cation of clonally related DNSE isolates. Of 9 DNSE isolates, 6 (66.7%) were Enterococcus faecium, 2 (22%) were E. faecalis, and 1 (11%) was E. gallinarum. Five isolates were available for further study (patients 4, 5, 6, 7, and 8) ( Table 2). The daptomycin MICs were confi rmed for these isolates by in-house prepared broth microdilution in cation-adjusted Muller Hinton broth plus calcium and by Etest (bioMérieux, Durham, NC, USA). Using strain typing by repPCR (DiversiLabTM; bioMérieux), we found that there was no genetic relatedness between the 2 E. faecium isolates available for typing, but the 2 E. faecalis were 97.7% similar by repPCR. These 2 isolates were also 98.5% related to a third daptomycin-nonsusceptible E. faecalis isolate from a patient who had received 90 days of daptomycin treatment before isolation of the DNSE. No epidemiologic link was found between these 3 patients, and 2 of the cases were identifi ed on the fi rst day of hospitalization, 6 months (patient 5) and 1 year (case 4) after the isolation of the original DNSE in the third patient (not included in this case series).
Four (44.4%) patients died while receiving therapy for DNSE (Table 1). Each patient had multiple concurrent conditions, and cause of death could not be attributed solely to DNSE. (Table 1). Of the 5 patients who survived, the clinical response to treatment of DNSE infection could not be determined for 3 patients because of multiple concurrent conditions and polymicrobial infection. However, 1 patient with cholangitis, from whom DNSE were isolated from a bile culture, improved clinically despite receiving antimicrobial agents that were inactive against DNSE. The second clinically evaluable patient had asymptomatic bacteriuria associated with DNSE, did not receive any antimicrobial therapy, and remained clinically stable. Follow-up urine samples were cultured for 1 of the 5 surviving patients (patient 5); the result was negative.

Conclusions
Two existing studies of de novo development of daptomycin nonsusceptibility describe 1 case each (6,7). To our knowledge, this study analyzes one of the largest series of DNSE isolates in patients with no prior exposure to daptomycin.
The mechanism for daptomycin nonsusceptibility in enterococci is poorly understood (8). A recent study found that 25% of Enterococcus spp. isolated from beef products were DNSE (9). Spread of these DNSE from agriculture to humans through the food chain may be a mechanism by which DNSE are emerging (10)(11)(12). Of note, in our case series, 3 patients (patients 2, 7, and 8) had a history of exposure to livestock: 1 (patient 2) was a veterinarian; 2 (patients 7 and 8) had histories of farm exposure. Three (patients 4, 5, and 7) reported frequent ingestion of beef. We recommend further investigation of these observations by case-control study.
The limitations of our study include the retrospective observational study design, the small number of cases identifi ed, and lack of a comparison group. Case-control studies could better defi ne risk factors associated with emergence of DNSE. Clinicians should be aware of the possibility of serious infections associated with DNSE even when there is no history of prior daptomycin therapy. Dr Kelesidis is an infectious disease specialist at the UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, USA. His research interests include microbial pathogenesis and HIV/AIDS.