A current perspective on daptomycin for the clinical microbiologist

Abstract

Daptomycin is a lipopeptide antimicrobial with in vitro bactericidal activity against Gram-positive bacteria that was first approved for clinical use in 2004 in the United States. Since this time, significant data have emerged regarding the use of daptomycin for the treatment of serious infections, such as bacteremia and endocarditis, caused by Gram-positive pathogens. However, there are also increasing reports of daptomycin nonsusceptibility, in Staphylococcus aureus and, in particular, Enterococcus faecium and Enterococcus faecalis. Such nonsusceptibility is largely in the context of prolonged treatment courses and infections with high bacterial burdens, but it may occur in the absence of prior daptomycin exposure. Nonsusceptibility in both S. aureus and Enterococcus is mediated by adaptations to cell wall homeostasis and membrane phospholipid metabolism. This review summarizes the data on daptomycin, including daptomycin's unique mode of action and spectrum of activity and mechanisms for nonsusceptibility in key pathogens, including S. aureus, E. faecium, and E. faecalis. The challenges faced by the clinical laboratory in obtaining accurate susceptibility results and reporting daptomycin MICs are also discussed.

Fig 1

Daptomycin structure (A) and interaction with the cytoplasmic membrane (B).

Fig 2

MIC distributions for Gram-positive clinical isolates collected in Europe, North America, and South America in 2002, before the introduction of daptomycin for clinical use. (Based on data from reference .)

Fig 3

Percent probability of pharmacokinetic-pharmacodynamic target attainment for area under the curve targets of 180 for S. aureus (A) and 48 for E. faecalis (B). Data were generated from Monte Carlo analysis by applying a total drug AUC/MIC criterion of 180 or 48 for efficacy, based on murine thigh and thigh and renal models for S. aureus and E. faecalis, respectively. A 4-mg/kg q24h dose of daptomycin with an AUC of 494 ± 75 μg · h/ml was used in this simulation.

Fig 4

Mutations in MprF identified in daptomycin-NS S. aureus. MprF consists of an N-terminal flippase domain and a C-terminal phosphatidylglycerol lysylination domain. Mutations have been identified in both domains, as outlined in the following references: a, reference ; b, reference ; c, reference ; d, reference ; e, reference ; f, reference ; g, reference ; h, reference ; i, reference .