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The emergence of glycopeptide reduced susceptibility and resistance in Staphylococcus aureus strains is a growing clinical problem that poses significant clinical challenges in treatment. Its development is a complex and novel process involving many subtle physiological changes in the micro-organism. Daptomycin is the first cyclic lipopeptide approved for clinical use. Unlike most other antimicrobials, a trend towards increased daptomycin resistance has not been reported, although several cases of daptomycin non-susceptibility have been reported. The present review will present the available evidence on daptomycin resistance of S. aureus , with particular attention to its development. In addition to a literature overview, we have compiled the reported cases of daptomycin non-susceptibility to shed light on possible clinical mechanisms of resistance. In the 36 reports describing 62 clinical cases, infections caused by meticillin-resistant S. aureus (MRSA) strains with a vancomycin minimum inhibitory concentration (MIC) between 1mg/L and 2mg/L often led to vancomycin treatment failure, which may be associated with the development of non-susceptibility to daptomycin. Additional evidence suggests that underdosage of daptomycin is an important clinical aspect that merits further study. The current analysis highlights the importance of determining the MIC when using vancomycin to treat patients with severe S. aureus infections and that when failure is suspected, testing for heterogeneous vancomycin-intermediate S. aureus (hVISA) may also be necessary. Whilst further investigation is needed, it can be hypothesised that MRSA strains become hVISA during prolonged bacteraemia, which may predispose to the development of daptomycin resistance.

We report the results of 8 years (2005–2012) of the Daptomycin Surveillance Programme Worldwide. Consecutive non-duplicate bacterial isolates (prevalence design) were collected from patients with documented infections in 410 medical centres and were susceptibility tested by reference broth microdilution methods. A total of 164 457 Gram-positive isolates were evaluated, including 97 542 Staphylococcus aureus , 21 413 coagulase-negative staphylococci (CoNS), 29 619 enterococci and 15 883 β-haemolytic streptococci. The prevalence of daptomycin-non-susceptible isolates was extremely low for all species in all geographic regions. Overall, the highest occurrence of non-susceptible isolates was observed among CoNS (0.19%), followed by Enterococcus faecium (0.18%), S. aureus (0.05%), Enterococcus faecalis (0.02%) and β-haemolytic streptococci (0.00%). Moreover, no trend towards increased daptomycin resistance (non-susceptibility) was observed for any species in any geographic region during the study interval. Against S. aureus , the daptomycin MIC 50/90 was 0.25/0.5 mg/L in all geographic regions (99.95% susceptible overall). Only 53 daptomycin-non-susceptible S. aureus isolates were observed and the vast majority (49; 92.5%) had a daptomycin MIC value only 1 log 2 dilution above the published susceptible breakpoint. Daptomycin was also active against CoNS (MIC 50/90 , 0.25/0.5 mg/L; 99.81% susceptible), E. faecalis (MIC 50/90 , 1/2 mg/L; 99.98% susceptible), E. faecium (MIC 50/90 , 2/4 mg/L; 99.82% susceptible) including vancomycin-non-susceptible isolates (4521 isolates; MIC 50/90 , 2/2 mg/L; 99.76% susceptible), and β-haemolytic streptococci (MIC 50/90 , ≤0.06/0.25 mg/L; 100.0% susceptible). In conclusion, daptomycin has remained very active against indicated species worldwide, and no significant year-to-year or regional variation in daptomycin activity has been detected.