Daptomycin microbiology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Abdurahman Khalil, M.D. [2]
Daptomycin belongs to the cyclic lipopeptide class of antibacterials. Daptomycin has clinical utility in the treatment of infections caused by aerobic, Gram-positive bacteria. The in vitro spectrum of activity of daptomycin encompasses most clinically relevant Gram-positive pathogenic bacteria.
Daptomycin exhibits rapid, concentration-dependent bactericidal activity against Gram-positive bacteria in vitro. This has been demonstrated both by time-kill curves and by MBC/MIC (minimum bactericidal concentration/minimum inhibitory concentration) ratios using broth dilution methodology. Daptomycin maintained bactericidal activity in vitro against stationary phase S. aureus in simulated endocardial vegetations. The clinical significance of this is not known.
Mechanism of Action
The mechanism of action of daptomycin is distinct from that of any other antibacterial. Daptomycin binds to bacterial cell membranes and causes a rapid depolarization of membrane potential. This loss of membrane potential causes inhibition of DNA, RNA, and protein synthesis, which results in bacterial cell death.
Mechanism of Resistance
The mechanism(s) of daptomycin resistance is not fully understood. Currently, there are no known transferable elements that confer resistance to daptomycin.
Complicated Skin and Skin Structure Infection (cSSSI) Trials
The emergence of daptomycin non-susceptible isolates occurred in 2 infected patients across the set of Phase 2 and pivotal Phase 3 clinical trials of cSSSI. In one case, a non-susceptible S. aureus was isolated from a patient in a Phase 2 trial who received CUBICIN at less than the protocol-specified dose for the initial 5 days of therapy. In the second case, a non-susceptible Enterococcus faecalis was isolated from a patient with an infected chronic decubitus ulcer who was enrolled in a salvage trial.
S. aureus Bacteremia/Endocarditis and Other Post-Approval Trials
In subsequent clinical trials, non-susceptible isolates were recovered. S. aureus was isolated from a patient in a compassionate-use trial and from 7 patients in the S. aureus bacteremia/endocarditis trial [see Clinical Trials (14.2)]. An E. faecium was isolated from a patient in a vancomycin-resistant enterococci trial.
Interactions with Other Antibacterials
In vitro studies have investigated daptomycin interactions with other antibacterials. Antagonism, as determined by kill curve studies, has not been observed. In vitro synergistic interactions of daptomycin with aminoglycosides, β-lactam antibacterials, and rifampin have been shown against some isolates of staphylococci (including some methicillin-resistant isolates) and enterococci (including some vancomycin-resistant isolates).
Activity In Vitro and In Vivo
Daptomycin has been shown to be active against most isolates of the following Gram-positive bacteria both in vitro and in clinical infections, as described inIndications and Usage (1).
Gram-Positive Bacteria
Enterococcus faecalis (vancomycin-susceptible isolates only)
Staphylococcus aureus (including methicillin-resistant isolates)
Streptococcus dysgalactiae subsp. equisimilis
The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following Gram-positive bacteria exhibit an in vitrominimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for daptomycin versus the bacterial genus (Table 9). However, the efficacy of CUBICIN in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.
Gram-Positive Bacteria
Corynebacterium jeikeium
Enterococcus faecalis (vancomycin-resistant isolates)
Enterococcus faecium (including vancomycin-resistant isolates)
Staphylococcus epidermidis (including methicillin-resistant isolates)
Susceptibility Testing Methods
When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility tests for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.
Dilution Techniques
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized broth test method2,3 with the broth adjusted to a calcium content of 50 mg/L. The use of the agar dilution method is not recommended with daptomycin3. The MICs should be interpreted according to the criteria listed in Table 9.
A report of "Susceptible" indicates that the antimicrobial is likely to inhibit the growth of the pathogen if the antimicrobial compound reaches the concentration at the infection site necessary to inhibit growth of the pathogen.
Diffusion Technique
Quantitative methods that require measurement of zone diameters have not been shown to provide reproducible estimates of the susceptibility of bacteria to daptomycin. The use of the disk diffusion method is not recommended with daptomycin3,4.
Quality Control
Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test2,3. Standard daptomycin powder should provide the ranges of MIC values noted in Table 10.
References
http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021572s033lbl.pdf