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PubMed2006

Emergence of a clinical daptomycin-resistant Staphylococcus aureus isolate during treatment of methicillin-resistant Staphylococcus aureus bacteremia and osteomyelitis.

The emergence of a clinically daptomycin-resistant Staphylococcus aureus isolate occurred during treatment of methicillin-resistant S. aureus bacteremia and probable vertebral osteomyelitis. The breakthrough isolate was indistinguishable from pretreatment daptomycin-susceptible isolates by pulsed-field gel electrophoresis. Daptomycin nonsusceptibility was confirmed by MIC and time-kill curve analyses.

Anti-Bacterial Agents↗
PubMed1989

Comparison of in vitro activity of daptomycin, vancomycin and fluoroquinolones in broth and serum against Staphylococcus epidermidis as determined by time-kill kinetics.

We compared the activity of daptomycin, vancomycin and fluoroquinolones against 46 blood isolates of Staphylococcus epidermidis. Daptomycin was more rapidly bactericidal than vancomycin and demonstrated less of an inoculum effect than the quinolones. Time-kill kinetic studies demonstrated no significant differences in survival in broth as compared to 50% human serum-supplemented broth. Daptomycin and the quinolones are suitable for study in clinical trials of efficacy as therapeutic alternatives to vancomycin for S. epidermidis infections.

Anti-Bacterial Agents↗
PubMed1990

Daptomycin versus vancomycin treatment for Staphylococcus aureus bacteremia in a murine model.

Daptomycin (LY 146032), a new lipopeptide antimicrobial agent with activity against gram-positive bacteria, was compared to vancomycin in the treatment of staphylococcal bacteremia in a murine model. Two hundred and ninety-nine mice were inoculated with 1 x 10(8) bacteria by the tail vein, and treatment was begun 3 days later. Two dosage regimens of each drug were used: 10 mg/kg and 5 mg/kg administered every 12 h for 14 days. A control group received no therapy. Survival was determined 31 days after inoculation. There was no significant difference in survival in any of the four treatment groups. The survival in all treatment groups was significantly greater than in the control group. Serum levels of daptomycin remained longer in the therapeutic range than serum levels of vancomycin. In the murine model of staphylococcal disease, daptomycin treatment was as effective as treatment with vancomycin.

Animals↗
PubMed2006

Development of daptomycin resistance in a bone marrow transplant patient with vancomycin-resistant Enterococcus durans.

Daptomycin has demonstrated antibacterial activity against several antibiotic-resistant strains, including vancomycin-resistant enterococci. A paucity of data exists concerning in vivo development of daptomycin resistance of enterococci. We describe an allogeneic bone marrow transplant patient, who was found to have vancomycin-resistant Enterococcus durans bacteremia, which subsequently developed resistance to daptomycin.

Bone Marrow Transplantation↗
PubMed2004

Daptomycin.

Daptomycin, the first in a class of agents known as lipopeptides, is a novel antimicrobial agent used for the treatment of gram-positive infections. The compound has a distinctive mechanism of action that exerts its bactericidal activity by disrupting plasma membrane function without penetrating into the cytoplasm. The agent has received much interest because of its activity against multidrug-resistant, gram-positive bacteria such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and glycopeptide-intermediate and -resistant S. aureus. Daptomycin demonstrates concentration-dependent killing and is eliminated primarily by glomerular filtration. It was approved in September 2003 for the treatment of complicated skin and soft tissue infections. It has a safety profile similar to other agents commonly administered to treat gram-positive infections. Daptomycin is a welcome addition to the antimicrobial armamentarium for the treatment of bacterial infections. Further clinical experience with this compound will help define its role in the treatment of resistant gram-positive organisms.

Animals↗
PubMed2006

Pharmacokinetics of daptomycin in a critically ill adolescent with vancomycin-resistant enterococcal endocarditis.

Daptomycin is a lipopeptide antibiotic active against multidrug-resistant gram-positive organisms. Our search of the literature found no published pediatric pharmacokinetic data. We report the use of pharmacokinetic analysis of daptomycin in a 13-year-old boy with vancomycin-resistant Enterococcus faecium endocarditis. Pharamcokinetic parameters were found to be significantly different from published adult parameters, such as a faster elimination rate, shorter half-life, and increased clearance. These age-related differences in the pharmacokinetic profile of daptomycin have significant dosing implications. As the use of this drug for off-label indications and in pediatric populations increases, it is important for clinicians to better understand the drug's pharmacokinetic profile in these patient populations.

Adolescent↗
PubMed1995

Effect of polymyxin B nonapeptide on daptomycin permeability and cell surface properties in Pseudomonas aeruginosa, Escherichia coli, and Pasteurella multocida.

The present study was carried out to determine if sensitization of Gram-negative bacteria to the polyanionic antibiotic daptomycin by cationic molecules can be explained on the basis of decreased cell surface charge in order to better understand intrinsic resistance. Turbidimetric assessments of batch cultural growth kinetics revealed the outer membrane permeabilizer polymyxin B nonapeptide sensitized Pseudomonas aeruginosa and Escherichia coli to the hydrophobic probe novobiocin, whereas little or no sensitization was observed for two surface hydrophobicity variants of Pasteurella multocida. Polymyxin B nonapeptide and daptomycin synergistically inhibited growth of P. aeruginosa only. A hydrocarbon adherence assay revealed permeabilizing concentrations of polymyxin B nonapeptide increased cell surface hydrophobicity of P. aeruginosa and the hydrophobic P. multocida variant, while E. coli and the hydrophilic P. multocida variant remained unaffected. Measurement of cellular electrophoretic mobility showed polymyxin B nonapeptide permeabilization of P. aeruginosa to daptomycin occurred concomitantly with a significant decrease in cell surface charge, while no such sensitization occurred in organisms which failed to undergo polymyxin B nonapeptide-induced surface charge decreases. These data suggest that sensitization of Gram-negative bacteria to polyanionic lipopeptides by growth in the presence of polycationic outer membrane permeabilizers such as polymyxin B nonapeptide is dependent on diminution of overall cell surface charge and polarity, thereby allowing outer cell envelope permeation.

Cell Membrane↗
PubMed2004

In vitro activities of the new semisynthetic glycopeptide telavancin (TD-6424), vancomycin, daptomycin, linezolid, and four comparator agents against anaerobic gram-positive species and Corynebacterium spp.

Telavancin is a new semisynthetic glycopeptide anti-infective with multiple mechanisms of action, including inhibition of bacterial membrane phospholipid synthesis and inhibition of bacterial cell wall synthesis. We determined the in vitro activities of telavancin, vancomycin, daptomycin, linezolid, quinupristin-dalfopristin, imipenem, piperacillin-tazobactam, and ampicillin against 268 clinical isolates of anaerobic gram-positive organisms and 31 Corynebacterium strains using agar dilution methods according to National Committee for Clinical Laboratory Standards procedures. Plates with daptomycin were supplemented with Ca(2+) to 50 mg/liter. The MICs at which 90% of isolates tested were inhibited (MIC(90)s) for telavancin and vancomycin were as follows: Actinomyces spp. (n = 45), 0.25 and 1 microg/ml, respectively; Clostridium difficile (n = 14), 0.25 and 1 microg/ml, respectively; Clostridium ramosum (n = 16), 1 and 4 microg/ml, respectively; Clostridium innocuum (n = 15), 4 and 16 microg/ml, respectively; Clostridium clostridioforme (n = 15), 8 and 1 microg/ml, respectively; Eubacterium group (n = 33), 0.25 and 2 microg/ml, respectively; Lactobacillus spp. (n = 26), 0.5 and 4 microg/ml, respectively; Propionibacterium spp. (n = 34), 0.125 and 0.5 microg/ml, respectively; Peptostreptococcus spp. (n = 52), 0.125 and 0.5 microg/ml, respectively; and Corynebacterium spp. (n = 31), 0.03 and 0.5 microg/ml, respectively. The activity of TD-6424 was similar to that of quinupristin-dalfopristin for most strains except C. clostridioforme and Lactobacillus casei, where quinupristin-dalfopristin was three- to fivefold more active. Daptomycin had decreased activity (MIC > 4 microg/ml) against 14 strains of Actinomyces spp. and all C. ramosum, Eubacterium lentum, and Lactobacillus plantarum strains. Linezolid showed decreased activity (MIC > 4 microg/ml) against C. ramosum, two strains of C. difficile, and 15 strains of Lactobacillus spp. Imipenem and piperacillin-tazobactam were active against >98% of strains. The MICs of ampicillin for eight Clostridium spp. and three strains of L. casei were >1 microg/ml. The MIC(90) of TD-6424 for all strains tested was </=2 microg/ml. TD-6424 has potential for use against infections with gram-positive anaerobes and deserves further clinical evaluation.

Adult↗
PubMed1994

Comparison of quantitative whole-body autoradiographic and tissue dissection techniques in the evaluation of the tissue distribution of [14C]daptomycin in rats.

Quantitative whole-body autoradiography (QWBA) was evaluated and compared to tissue dissection/liquid scintillation counting (TD/LSC) techniques by determining the tissue distribution of radiocarbon in rats following iv administration of the antibiotic [14C]daptomycin (LY146032). QWBA, using computer-assisted video-image analysis, was initially evaluated by characterizing and calibrating commercial standards to blood and brain, kidney, liver, and lung homogenates. Frozen (carboxymethyl)cellulose blocks containing tissue homogenates spiked with [14C]glucose (370-37,000 Bq/g or 10-1000 nCi/g) were sectioned and optical densities (OD) measured. Characterization of QWBA included repeated measures data analysis to determine the significance of tissue type and intra- and inter-section and block variability. Regression models relating OD to radiocarbon concentration were also used to calibrate commercial standards for use in QWBA analyses. Results indicated that there were no substantial differences between OD readings from different tissues; however, the greatest source of variation in OD reading was section thickness. Because quantitative variations were largely attributed to section thickness, an internal standard (IS), consisting of liver homogenates spiked with [14C]glucose, was evaluated as a correction factor. Tissue concentrations of radiocarbon in male Fischer 344 rats were evaluated by QWBA and TD/LSC techniques 0.25 h following a single iv 10 mg/kg dose of [14C]daptomycin. Results indicated that tissue concentrations of radiocarbon obtained by QWBA, normalized using an IS, were comparable to those obtained by TD/LSC.

Amino Acid Sequence↗
PubMed1990

In vitro activity of daptomycin-metronidazole combinations against mixed bacterial cultures: reduced activity of metronidazole against Bacteroides species in the presence of Enterococcus faecalis.

The in vitro activity of daptomycin-metronidazole combinations against mixed cultures of gram-positive facultative cocci and strains of the Bacteroides fragilis group was investigated. Metronidazole did not influence the high activity of daptomycin against strains of Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus faecalis in the absence or presence of the co-cultured Bacteroides strains. In contrast, the Enterococcus faecalis isolates protected the co-cultured Bacteroides strains against the killing effect of metronidazole, even at a concentration four- or eightfold the MIC of metronidazole. Killing curve experiments confirmed this protective effect of different isolates of Enterococcus faecalis.

Anti-Bacterial Agents↗
PubMed2005

Heterologous production of daptomycin in Streptomyces lividans.

Daptomycin and the A21978C antibiotic complex are lipopeptides produced by Streptomyces roseosporus and also in recombinant Streptomyces lividans TK23 and TK64 strains, when a 128 kbp region of cloned S. roseosporus DNA containing the daptomycin gene cluster is inserted site-specifically in the phiC31 attB site. A21978C fermentation yields were initially much lower in S. lividans than in S. roseosporus, and detection was complicated by the production of host metabolites. However A21978C production in S. lividans was improved by deletion of genes encoding the production of actinorhodin and by medium optimization to control the chemical form of the calcium dependent antibiotic (CDA). This latter compound has not previously been chemically characterized as a S. lividans product. Adding phosphate to a defined fermentation medium resulted in formation of only the phosphorylated forms of CDA, which were well separated from A21978C on chromatographic analysis. Adjusting the level of phosphate in the medium led to an improvement in A21978C yield from 20 to 55 mg/l.

Anthraquinones↗
PubMed1990

Inhibition of peptidoglycan biosynthesis in Bacillus megaterium by daptomycin.

The effects of daptomycin on exponential phase cells of Bacillus megaterium were investigated. Bacteriostasis was observed for concentrations between 1 and 3 micrograms/ml and maximal rate of cell lysis at 10 micrograms/ml. At sublytic concentrations (1.5-3 micrograms/ml), the variations of the pools of UDP-N-acetylglucosamine and UDP-N-acetylmuramyl-pentapeptide, as well as the incorporation of (14C)-N-acetylglucosamine into peptidoglycan were studied. From the results it was concluded that the lethal target of daptomycin could be a metabolic step between glucosamine 6-phosphate and UDP-N-acetylglucosamine.

Acetylglucosamine↗
PubMedDate not supplied

Pacemaker-induced Staphylococcus aureus mitral valve acute bacterial endocarditis complicated by persistent bacteremia from a coronary stent: Cure with prolonged/high-dose daptomycin without toxicity.

Continuous high-grade Staphylococcus aureus bacteremia suggests acute bacterial endocarditis (ABE), a protected focus, ie, an abscess, or a device-related infection. Daptomycin was curative of S. aureus ABE and coronary stent-related bacteremia. Prolonged high-dose daptomycin therapy (12 mg/kg per day for 41 days) is not associated with any toxicity. Persistent S. aureus bacteremia in ABE should suggest myocardial or perivalvular abscess. If intracardiac abscess can be ruled out and there is no extracardiac source of the S. aureus bacteremia, then a device-related infection should be considered.

Aged↗
PubMed2007

Eosinophilic pneumonia induced by daptomycin.

We present a case of drug-induced eosinophilic pneumonia resulting from intravenous daptomycin being used as therapy for recurrent methicillin-sensitive Staphlococcus aureus endocarditis. The patient developed hypoxic respiratory failure requiring intubation and mechanical ventilation. Daptomycin therapy was discontinued immediately, and the patient improved significantly after the administration of intravenous corticosteroids allowing for extubation 3 days later.

Anti-Bacterial Agents↗
PubMed2005

Natural products to drugs: daptomycin and related lipopeptide antibiotics.

Daptomycin (Cubicin) is a lipopeptide antibiotic approved in the USA in 2003 for the treatment of skin and skin structure infections caused by Gram-positive pathogens. It is a member of the 10-membered cyclic lipopeptide family of antibiotics that includes A54145, calcium-dependent antibiotic (CDA), amphomycin, friulimicin, laspartomycin, and others. This review highlights research on this class of antibiotics from 1953 to 2005, focusing on more recent studies with particular emphasis on the interplay between structural features and antibacterial activities; chemical modifications to improve activity; the genetic organization and biosynthesis of lipopeptides; and the genetic engineering of the daptomycin biosynthetic pathway to produce novel derivatives for further chemical modification to develop candidates for clinical evaluation.

Anti-Bacterial Agents↗
PubMed2006

Daptomycin for the treatment of vancomycin resistant Enterococcus faecium bacteremia.

The best therapeutic options for serious infections due to vancomyci resistant Enterococcus (VRE) remain unclear. We describe the successful treatment of vancomycin resistant Enterococcus faecium bacteremia in 2 patients using daptomycin. We also briefly review the literature on antibiotic options for VRE infection including the use of daptomycin.

Aged↗
PubMed1991

Effects of vancomycin, teicoplanin, daptomycin and coumermycin on normal immune capabilities.

Vancomycin, teicoplanin, daptomycin, and coumermycin were investigated for immunomodulatory activity on both humoral and cell-mediated immune responses in Balb/c mice. All four antibiotics did not produce any interference with these responses as measured by hemolytic plaque assay and delayed-type hypersensitivity to sheep red blood cells. The administration of these antibiotics for seven days did not affect the peripheral blood leukocyte count or spleen weights. When these antibiotics were tested for their interaction with human polymorphonuclear phagocytic activity, no alteration in this activity was observed. These findings suggest that vancomycin, teicoplanin, daptomycin, and coumermycin may be safely used for the treatment of infections without altering host-defence mechanisms.

Aminocoumarins↗
PubMed2004

Daptomycin: another novel agent for treating infections due to drug-resistant gram-positive pathogens.

Daptomycin is a novel cyclic lipopeptide antibiotic that provides rapid bactericidal activity against gram-positive pathogens in vitro, including methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus, vancomycin-resistant S. aureus, penicillin-resistant Streptococcus pneumoniae, and ampicillin- and vancomycin-resistant enterococci. The United States Food and Drug Administration recently approved daptomycin for treatment of complicated skin and skin-structure infections. Its efficacy in the treatment of more-serious infections (e.g., staphylococcal bacteremia) is under investigation. As an intravenous agent that is administered once per day, it offers a convenient regimen for therapy that is continued after discharge, with a side effect profile that appears minimal and manageable. Spontaneous acquisition of resistance in vitro is rare, and hopefully this characteristic will extrapolate into the clinical setting. The rapid bactericidal activity, low potential for resistance, and promising safety profile associated with this agent will make it a useful addition to our growing armamentarium of antibiotics active against gram-positive pathogens.

Anti-Bacterial Agents↗