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PubMed1990

Clinical pharmacokinetics of daptomycin.

Daptomycin is a new lipopeptide antibiotic for which preliminary pharmacokinetic data in adults have been limited to normal healthy volunteers and patients with renal insufficiency. We report the clinical pharmacokinetics of the first and fifth doses of iv daptomycin 150 mg (2 mg/kg) q24h in a 29-year-old man being treated for a gram-positive cellulitis and thrombophlebitis. Individual pharmacokinetic parameters yielded similar results during doses one and five. The pharmacokinetic profile observed in our patient did not markedly differ from data obtained from healthy volunteers.

Adult↗
PubMed2004

Daptomycin - a novel antibiotic against Gram-positive pathogens.

Daptomycin is a novel member of a new class of antimicrobial agents used in treating resistant Gram-positive infections. These infections are becoming more commonplace and treatment options are limited. At present, daptomycin is approved for use in the US for complicated skin and skin-structure infections that are a common complication of surgery, diabetic foot ulcers, and burns. The most common causative organisms in these types of infections are Staphylococcus aureus, Streptococcus pyogenes, Streptococcus agalactiae, and Group C and G streptococci. Traditionally, these infections have been treated with penicillin and cephalosporins, but resistance to these agents is widespread and increasing. Of particular concern is the rapid increase in methicillin-resistant S. aureus (MRSA). The SENTRY Antimicrobial Surveillance Programme reported that approximately 30% of S. aureus isolates from skin and skin-structure infections were MRSA. The standard treatment for MRSA infections is vancomycin but resistance to this agent is also developing. There is a continuing need for the development of new antibiotics with Gram-positive activity, to combat multi-drug-resistant Gram-positive infections.

Animals↗
PubMed2006

Update on daptomycin: the first approved lipopeptide antibiotic.

Daptomycin, the first approved member of the lipopeptide antibiotic class, exhibits potent bactericidal in vitro activity against most Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus species and penicillin-resistant Streptococcus species. Since its approval in 2003 for the treatment of complicated skin and skin structure infections, several review articles have summarised daptomycin's mechanism of action, pharmacokinetics, pharmacodynamics, clinical trials and safety profiles. The objective of this paper is to summarise past information with a focus on the latest susceptibility data of isolates collected worldwide, new pharmacodynamic studies, clinical data regarding bacteraemia/endocarditis and postmarketing surveillance in the treatment of skin and skin-structure infections.

Animals↗
PubMed1991

Effect of daptomycin, metronidazole and mezlocillin combinations on mixed bacterial cultures involving facultative and anaerobic bacteria.

The in vitro activities of different daptomycin concentrations in combination with metronidazole (4 mg/l) or/and mezlocillin (8 mg/l) were investigated on mixed bacterial cultures involving gram-positive facultative cocci. Bacteroides fragilis group strains and Escherichia coli. When Streptococcus faecalis alone or together with E. coli was cultured with B. thetaiotaomicron the colony counts of the latter were 4 log units higher after incubation in the presence of daptomycin and metronidazole than when it was cultured alone. After the addition of mezlocillin, this effect disappeared and all 3 strains were killed. When the same antibiotic combinations were used in the presence of beta-lactamase producing Staphylococcus aureus, the activity of mezlocillin was decreased significantly. The colony counts of the co-cultured B. thetaiotaomicron and E. coli proved to be 2 log and 6 log higher, respectively, than those observed after they were cultured alone. The antimicrobial susceptibilities of the clinical isolates tested here in mixed cultures of up to 3 strains were modified significantly by interactions between the strains and the antibiotics used.

Bacteriological Techniques↗
PubMed1992

In-vitro activity of daptomycin against a worldwide collection of methicillin-resistant Staphylococcus aureus.

Minimum inhibitory and minimum bactericidal concentrations (MIC and MBC) of daptomycin and of vancomycin have been compared against 80 strains of methicillin-resistant Staphylococcus aureus isolated from many parts of the world. In the presence of 30 mg/l of Ca++, daptomycin at 4 mg/l killed all the strains tested, and was only slightly less active than vancomycin.

Anti-Bacterial Agents↗
PubMed2001

The kinetics of the alkaline degradation of daptomycin.

The aqueous degradation of daptomycin, a lipopeptide antibiotic, was investigated as a function of substrate concentration (0.5-10.0 mM), pH (9.0-10.5), buffer concentration (0.06-0.20 M borate, glycinate, or carbonate buffers), temperature (20-50 degrees C), and ionic strength (0.1-0.8). The primary degradation pathway was determined by electrospray-mass spectroscopy (ES-MS), Fourier transform infrared (FTIR), and fluorescence spectroscopy to be hydrolysis of the ester linkage between the C-terminus (kynurenine) and the side chain of the fourth residue (threonine). The reaction was first order with respect to time; however, the reaction order with respect to substrate concentration was <1 at substrate concentrations >1 mM. Insignificant buffer effect was observed. The reaction was subject to specific base catalysis. Activation parameters were E(a) = 13.6 kcal/K.mol, DeltaH++ = 13.0 kcal/K.mol, and DeltaS++ = -19.2 eu. The positive primary salt effect was observed with negative deviation at high concentration of salt. The magnitude of the salt effect depended on salt identities in the order sodium < potassium < calcium chloride.

Alkalies↗
PubMed2006

Mode of action of the new antibiotic for Gram-positive pathogens daptomycin: comparison with cationic antimicrobial peptides and lipopeptides.

With the steady rise in the number of antibiotic-resistant Gram-positive pathogens, it has become increasingly important to find new antibacterial agents which are highly active and have novel and diversified mechanisms of action. Two classes will be discussed here: the cationic antimicrobial peptides, which are amphiphilic in nature, targeting membranes and increasing their permeability; and lipopeptides, which consist of linear or cyclic peptides with an N-terminus that is acylated with a fatty acid side chain. One member of the cyclic lipopeptide family, the anionic molecule daptomycin, has been extensively studied and is the major focus of this review. Models will be presented on its mode of action and comparisons will be made to the known modes of action of cationic antimicrobial peptides and other lipopeptides.

Anti-Bacterial Agents↗
PubMed2004

Daptomycin structure and mechanism of action revealed.

Daptomycin kills otherwise antibiotic-resistant gram-positive pathogens and is the first lipopeptide antibiotic to reach the clinic. Elucidation of its 3D structure and mechanism of action, reported in this issue of Chemistry & Biology, will facilitate the design and engineering of new, potentially life-saving antibiotics.

Anti-Bacterial Agents↗
PubMed2007

Concentration-response relationships as a basis for choice of the optimal endpoints of the antimicrobial effect: daptomycin and vancomycin pharmacodynamics with staphylococci in an in vitro dynamic model.

The abilities of different indices of bacterial killing to ensure reasonable concentration-response relationships have been compared only in studies in vitro with fluoroquinolones. To ascertain the relevance of conclusions drawn in these studies to other antibiotic classes, five widely used indices that reflect the rate of initial killing (time to reduce the initial inoculum 10- and 100-fold-T(90%) and T(99%), respectively), the extent of killing (minimal number of surviving organisms-N(min)), and the entire antimicrobial effect (number of surviving organisms (N(t)) at the time t close to the end of the observation period (48 h in most experiments), and area between the control growth curve and the time-kill curve from zero point to t-ABBC) were examined with daptomycin (DAP)- and vancomycin (VAN)-exposed Staphylococcus aureus. To compare the pharmacodynamics of DAP and VAN and examine different parameters, killing kinetics of differentially susceptible S. aureus were studied over a wide range of ratios of area under the curve (AUC) to MIC. Killing kinetics of two clinical isolates, S. aureus 866 (MIC(DAP) 0.35 mg/L and MIC(VAN) 0.70 mg/L) and S. aureus 10 (MIC(DAP) 1.1mg/L and MIC(VAN) 1.3mg/L), were studied in an in vitro dynamic model that simulates human pharmacokinetics of DAP (as a single dose) and VAN (as two 12-h doses). Mono-exponential concentration decays were mimicked with half-lives of 9h (DAP) and 6h (VAN) at AUC/MIC ratios varying from 33 to 1150 h. T(90%), T(99%) and N(t) (at t=48 h) exhibited loose, if any, correlations with log AUC/MIC. Both ABBC (a direct measure of the antimicrobial effect) and N(min) (an inverse measure of the effect) correlated well with log AUC/MIC (r(2)=0.8-0.9). Based on the ABBC-log AUC/MIC relationships, the effects of DAP on S. aureus were predicted to be slightly greater than those of VAN at a given AUC/MIC ratio. The better abilities of ABBC and N(min) and the inability of T(90%) and T(99%) to provide reasonable AUC/MIC relationships with DAP and VAN support earlier findings reported with fluoroquinolones.

Anti-Bacterial Agents↗
PubMed2006

Daptomycin-rifampin for a recurrent MRSA joint infection unresponsive to vancomycin-based therapy.

A 54-y-old morbidly obese male presented with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia secondary to chronic right hip arthroplasty infection. Bacteremia persisted despite prolonged vancomycin-based therapy (MIC < or = 1 microg/ml) and prosthetic removal. Adding daptomycin-rifampin resolved bacteremia within 48 h; hip cultures remained negative post-discharge. This case describes alternative treatment for chronic MRSA infections.

Anti-Bacterial Agents↗
PubMed2006

Combination therapy with daptomycin, vancomycin, and rifampin for recurrent, severe bone and prosthetic joint infections involving methicillin-resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) infections are commonly treated with vancomycin (VAN) or another glycopeptide antibiotic. However, when vancomycin fails or infections recur, there are few other therapeutic options. Presented here are 2 cases where a novel combination of daptomycin, vancomycin, and rifampin resolved recurrent MRSA bone and prosthetic joint functions.

Anti-Bacterial Agents↗
PubMed1990

Experimental studies on nephrotoxicity and pharmacokinetics of LY 146032 (daptomycin) in rats.

The nephrotoxicity and pharmacokinetics of LY 146032 (daptomycin) were studied in an experimental rat model. Nephrotoxicity was assessed by measuring urinary loss of tubular cells and malate dehydrogenase. LY 146032 (10-250 mg/kg daily iv) led to a dose-dependent and reversible increase of cell elimination. The tubulo-toxic threshold dose is stated to be 10 mg/kg daily. Nephrotoxicity induced by LY 146032 can be reduced by coadministration of fosfomycin or D-glucaro-1.5-lactam, and enhanced by combination with tobramycin. LY 146032 accumulated in renal tissue during repeated administration. Electron microscopy revealed histopathological changes in the kidneys. Therefore the nephrotoxic potential of LY 146032 should be taken into consideration in clinical trials.

Animals↗
PubMed1989

In vitro activities of daptomycin and other antimicrobial agents against vancomycin-resistant gram-positive bacteria.

A comparative evaluation of daptomycin and eight other antimicrobial agents was performed by the agar dilution technique with 56 strains of vancomycin-resistant gram-positive bacteria, including Leuconostoc, Lactobacillus, and Pediococcus spp. Erythromycin, deptomycin, clindamycin, and gentamicin exhibited the greatest activities, whereas penicillin, ampicillin, and cefotaxime showed moderate activities. The organisms were all highly resistant to vancomycin and cefoxitin.

Anti-Bacterial Agents↗
PubMed1991

Activity of mersacidin, a novel peptide, compared with that of vancomycin, teicoplanin, and daptomycin.

Mersacidin, a new peptide antibiotic, was four- to eightfold less active (MIC for 90% of isolates, 8 micrograms/ml) than vancomycin, teicoplanin, or daptomycin against Staphylococcus aureus. Coagulase-negative staphylococci were inhibited by 8 micrograms/ml, and the MICs of mersacidin for hemolytic streptococci and Streptococcus pneumoniae were 4 to 8 micrograms/ml. The mersacidin MICs for anaerobic organisms were as follows: Clostridium perfringens, 4 micrograms/ml; Propionibacterium acnes, 8 micrograms/ml; peptococci, 1 microgram/ml; and peptostreptococci, 8 micrograms/ml. Mersacidin had no activity against members of the family Enterobacteriaceae, Neisseria and Haemophilus species, or Pseudomonas aeruginosa. The size of the inoculum, the pH of the assay (5.5 to 7.5), the type of medium, and the anaerobic conditions had minimal effects on the MICs and MBCs of mersacidin. Overall, mersacidin proved less active than available glycopeptides and peptolides.

Anti-Bacterial Agents↗
PubMed2004

In vitro activity of daptomycin against gram-positive European clinical isolates with defined resistance determinants.

The in vitro activity of daptomycin against 337 gram-positive European clinical isolates with known resistance genes was determined. The MIC ranges for Staphylococcus aureus, enterococci, pneunococci, and streptococci were 0.03 to 1, 0.25 to 8, 0.12 to 1, and 0.06 to 8 micro g/ml, respectively. For only one streptococcus isolate and seven enterococcus isolates was the MIC 8 micro g/ml.

Anti-Bacterial Agents↗