In vivo daptomycin efficacy against experimental vancomycin-resistant Enterococcus faecium endocarditis

Objectives: Daptomycin has become a first-line therapeutic option for vancomycin-resistant Enterococcus faecium infective endocarditis (IE). Although high doses (>= 8 mg/kg) are often recommended, optimal doses, particularly for strains with MICs close to the susceptibility breakpoint (4 mg/L), are still debated. Methods: Daptomycin efficacy at doses equivalent to 8 mg/kg daptomycin (DAP8) and 12 mg/kg daptomycin (DAP12) in humans was evaluated in a rabbit model of aortic valve IE induced by 10(8) cfu of E. faecium reference strain Aus0004 (daptomycin MIC = 2 mg/L) or its in vitro mutant strain Mut4 (daptomycin MIC = 4 mg/L). Treatment began 48 h post-inoculation and lasted 5 days. Results: With Aus0004, the median log(10) cfu/g of vegetations was significantly lower after DAP8 and DAP12 versus controls [6.05 (n = 12) and 2.15 (n = 10) versus 9.14 (n = 11), respectively; P < 0.001], with DAP12 being more effective than DAP8 concerning vegetation bacterial load (P < 0.001) and percentages of sterile vegetations (100% versus 0%, respectively; P < 0.001). Daptomycin-resistant Aus0004 mutants were detected in 8.3% of DAP8-treated vegetations. With Mut4, the median log10 cfu/g of vegetations was significantly lower after DAP8 and DAP12 versus controls [7.7 (n = 11) and 6.95 (n = 10) versus 9.59 (n = 11), respectively; P = 0.001 and P = 0.002], without any between-dose difference, but no vegetation was sterile. Moreover, 7 of 11 (63.6%) and 7 of 9 (77.8%) vegetations contained resistant mutants after DAP8 and DAP12, respectively. Conclusions: DAP12 was the most successful strategy against IE due to a WT E. faecium strain (daptomycin MIC = 2 mg/L). To treat IE strains with MIC = 4 mg/L, DAP8 or DAP12 monotherapy was poorly effective with the risk of resistant mutant emergence. Reassessment of the daptomycin susceptibility breakpoint for enterococci seems necessary.