Daptomycin: a novel cyclic lipopeptide antimicrobial.

PURPOSE: The development, activity, pharmacokinetics, pharmacodynamics, clinical efficacy, adverse effects, and dosage and administration of daptomycin are reviewed. SUMMARY: Daptomycin, a novel cyclic lipopeptide antimicrobial, is bactericidal against a range of gram-positive bacteria, including many multiple-drug-resistant isolates. It has only minimal activity against anaerobic bacteria and no activity against gram-negative bacteria. Daptomycin exhibits linear pharmacokinetics, and the plasma concentration-versus-time relationship is best described by a two-compartment model with first-order elimination. The initial bactericidal activity is rapid, extensive, and concentration related. In clinical trials, daptomycin has shown efficacy in treating complicated skin and skin-structure infections (CSSSIs); the drug carries FDA-approved labeling for same. The adverse effects of daptomycin appear comparable to those of vancomycin and semisynthetic penicillins. The dosage for CSSSIs is 4 mg/kg by i.v. infusion every 24 hours. CONCLUSION: Daptomycin is bactericidal against gram-positive organisms and offers an option in the treatment of CSSSIs.     

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.     

Mulundocandin, a new lipopeptide antibiotic. II. Structure elucidation

The structure of a new antifungal antibiotic, mulundocandin, C48H77N7O16, was elucidated by high field NMR experiments e.g., homo- and heteronuclear correlation spectra, distortionless enhancement by polarization transfer (DEPT) spectra as well as nuclear Overhauser effect. The compound is a lipopeptide antibiotic belonging to the echinocandin class.     

A54145, a new lipopeptide antibiotic complex: isolation and characterization

A54145 is a complex of acidic lipopeptide antibiotics which are produced by Streptomyces fradiae and are active against Gram-positive bacteria. The A54145 complex was isolated by adsorption on Diaion HP-20 nonfunctionalized macroreticular resin and/or ion exchange on Amberlite IRA-68 anion exchange resin. Antibacterial factors A, A1, B, B1, C, D, E, and F were obtained in purified form by repeated preparative reverse phase HPLC on C8 and/or C18 bonded-phase supports. The molecular formulae of the factors are C72H109N17O27 (factors A and A1), C73H111N17O27 (factors B, B1, C, and D), C74H113N17O27 (factor E), and C71H107N17O27 (factor F). The identities of the acyl side chains were established as 8-methylnonanoyl (factors F, A, and B1), n-decanoyl (factors A1 and B), and 8-methyldecanoyl (factors C, D, and E).     

A54145, a new lipopeptide antibiotic complex: microbial and chemical modification

A54145 is a complex of acidic lipopeptide antibiotics produced by Streptomyces fradiae NRRL 18158, NRRL 18159, and NRRL 18160. Each antibiotic factor consists of a peptide core bearing an N-terminal acyl substituent. N-Lys-tert-BOC-protected A54145 complex was deacylated by Actinoplanes utahensis; three protected core peptides were isolated. A54145 antibiotic analogs were synthesized by acylation of the tryptophan N-terminus with 2,4,5-trichlorophenyl active esters, followed by deblocking with trifluoroacetic acid.     

A54145 a new lipopeptide antibiotic complex: microbiological evaluation

A54145 complex is made up of eight factors; A, A1, B, B1, C, D, E, and F which were active in vitro (MIC 0.25 approximately greater than 32 micrograms/ml) against Gram-positive aerobic organisms. The complex, factor B and B1 were found to be active against two strains of Clostridium perfringens. A calcium dependence study on some of the factors showed that their in vitro antibacterial activity was greatly enhanced by the presence of calcium (50 mg/liter) in the media. Resistance build-up was seen when Staphylococcus sp. and Streptococcus sp. were passed seven times in the presence of sublethal concentrations of A54145 antibiotics. This resistance disappeared immediately when the resistant organisms were passed in the absence of the antibiotics. Factor A was very effective against Staphylococcus aureus and Streptococcus pyogenes infections in mice (sc ED50s of 3.3 approximately 2.4 mg/kg x 2, respectively). Factor B was more active against S. pyogenes in vivo (sc ED50, 0.9 mg/kg x 2). Acute mouse toxicities were determined with these antibiotics. Semisynthetic derivatives were evaluated.     

A54145, a new lipopeptide antibiotic complex: discovery, taxonomy, fermentation and HPLC

A54145 is a complex of new lipopeptide antibiotics that inhibits Gram-positive bacteria and acts as a growth promotant for broiler chicks. Eight factors; A, B, C, D, E, F, A1 and B1; have been isolated and characterized. They contain four similar peptide nuclei, each of which is acylated with either an 2-decanoyl, n-decanoyl, or undecanoyl side chain. Taxonomic studies ascertained that the producing microorganism was a strain of Streptomyces fradiae. Fermentation studies determined that superior antibiotic yields were obtained in stirred bioreactors in a soybean flour-molasses medium employing a continuous glucose feed. These findings, interwoven with the selection of hyper-productive mutants, increased fermentation yields from less than 50 micrograms/ml to more than 1 mg/ml. An analytical HPLC system was developed for the identification and subsequent quantitation of each factor of the A54145 complex.     

Mulundocandin, a new lipopeptide antibiotic. I. Taxonomy, fermentation, isolation and characterization

Mulundocandin, a new lipopeptide antibiotic, was isolated from the culture broth of a strain of Aspergillus sydowi No. Y-30462. The antibiotic, obtained as a colorless amorphous powder having the molecular formula C48H77N7O16, is an antifungal antibiotic active against yeasts and filamentous fungi.     

A54145, a new lipopeptide antibiotic complex: factor control through precursor directed biosynthesis

A54145 is a complex of new lipopeptide antibiotics produced by Streptomyces fradiae. Eight factors, containing four similar peptide nuclei in combination with three different fatty acid acyl side chains, have been isolated from the natural fermentation and characterized. The nuclei differ only in valine/isoleucine and glutamate/3-CH3-glutamate substitutions at one or both of two locations on the peptide ring. Prior deacylation of all four nuclei with Actinoplanes utahensis had permitted chemical reacylation of each nucleus with new fatty acid acyl chains for structure-activity relationship studies. In an effort to induce the native biosynthesis of preferred factors or analogs by S. fradiae, the effect of fatty acid precursors on the fermentation was examined. Many fatty acids were extremely toxic to S. fradiae, which limited experiments to slow, continuous feeding of the lipids in stirred bioreactors that were equipped for on-line respiration analysis by mass spectrometry. These studies determined that precursing with aliphatic fatty acids of various chain lengths did enhance the biosynthesis of factors containing specific fatty acid acyl side chains. Caprate, for example, increased the n-decanoyl-containing factors from the natural level of approximately 14% to approximately 80%. The percentage of factors containing branched-chain fatty acid acyl substituents was also increased, in shaken-flask studies, by enriching the medium with valine or isoleucine. These amino acids additionally enhanced the percentage of nuclei containing either valine or isoleucine.     

Daptomycin: a review of properties, clinical use, drug delivery and resistance

Daptomycin is a branched cyclic anionic lipopeptide antibiotic that was discovered in the early 1980's but got the FDA approval only in 2003. This novel pharmaceutical molecule has demonstrated great in vitro activity against a wide range of aerobic and anaerobic gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. Daptomycin has a unique mechanism of action, not completely understood, involving a calcium-dependent dissipation of membrane potential leading to the release of intracellular ions from the cell and bacteria death. This antibiotic has been already approved for the treatment of patients with complicated skin and skin structure infections, right-sided endocarditis and bacteraemia. Local delivery of daptomycin is an emerging area of study. Current in vitro studies show that daptomycin can be eluted from polymethylmethacrylate, calcium sulfate and chitosan films. Emerging cases of resistance to daptomycin have been reported, commonly occurring by spontaneous mutations, and have been associated with prolonged use, osteomyelitis, acute myeloid leukemia and leucocyte adhesion deficiency syndrome. This review examines the most recent literature evidences on daptomycin molecular structure, mechanism of action, bacterial spectrum, clinical uses, local delivery, toxicity and resistance.     

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.     

Deacylation of A21978C, an acidic lipopeptide antibiotic complex, by Actinoplanes utahensis

A21978C, produced by Streptomyces roseosporus NRRL 11379, is an acidic lipopeptide antibiotic complex that inhibits Gram-positive bacteria. Individual factors of the complex possess an identical peptide core or "nucleus", and are differentiated by the distinctive fatty acid acyl group attached to the N-terminus of the nucleus. Certain members of the family Actinoplanaceae deacylated A21978C to yield the unaltered nucleus, which was then reacylated to form new analogs. Actinoplanes utahensis NRRL 12052 was the most efficient of these cultures, producing up to 500 micrograms of nucleus per ml of culture broth per hour. Eacylation was also accomplished with semi-pure and tert-butoxycarbonyl (tert-BOC)-A21978C. In the latter, the ornithine amino group was blocked to prevent formation of diacyl analogs during reacylation. The acylase was an endoenzyme present in submerged cultures of A. utahensis from less than 18 to greater than 168 hours of incubation. Whole cells suspended in phosphate buffer or entrapped in polyacrylamide gel also deacylated A21978C efficiently.     

Daptomycin in vitro susceptibility in European Gram-positive clinical isolates

The objective of this study was to determine the activity of daptomycin, a novel lipopeptide, against European Gram-positive isolates (n = 1539). The MIC(90)-values of daptomycin against Staphylococcus aureus isolates was 0.25 mg/L, against Enterococcus faecalis 4 mg/L, against Enterococcus faecium 8 mg/L, 0.25 mg/L against Staphylococcus epidermidis, and 0.25mg/L against Streptococcus pneumoniae. Daptomycin was equally potent against antibiotic-susceptible and resistant strains within a particular species. Based on a breakpoint of 1 mg/L for S. aureus and group A streptococci, all isolates tested were susceptible to daptomycin. Based on a breakpoint of 4 mg/L for vancomcyin-susceptible E. faecalis 99.7% of these isolates were susceptible to daptomycin.     

Quinolone, everninomycin, glycylcycline, carbapenem, lipopeptide and cephem antibacterials in clinical development

The development of antibacterials was a very successful endeavor in the pharmaceutical company repertoire through the late 1970s, when interest in investing in antibiotic research and development temporarily waned. More recently, there have been a number of failures in late stage development or post-launch of human antibiotics. The answer to the dilemma of less-than-desired success may be the introduction of novel classes of agents, as well as development of new agents in traditional classes. This review provides an overview of the various "miscellaneous" antibacterials in development, excluding glycopeptides, macrolides, ketolides, and oxazolidinones. Among the agents highlighted in this review are the clinical candidates of quinolones, everninomycins, carbapenems, lipopeptides, glycylcyclines, and cephems. In several cases, certain quinolone agents described in this review will have been approved for marketing before press time.     

Daptomycin and tigecycline: a review of clinical efficacy in the antimicrobial era

There is a clinical need for new treatment options as a result of continued increase in the expression of resistance among bacterial pathogens. A number of compounds currently in development show promise. However, in some cases, there is concern that resistance may develop quickly to new compounds that are based on existing antimicrobial agents. Therefore, daptomycin, a novel lipopeptide with a unique mode of action, is of particular interest. It has rapid bactericidal activity against growing and stationary-phase bacteria, once-daily dosing regimen, and has a low potential for the development of resistance. It has been approved for the treatment of complicated skin and soft tissue infections caused by Gram-positive bacteria, and registration for treatment of infective endocarditis and bacteraemia is anticipated. Daptomycin is a welcome addition to the antimicrobial armamentarium for the treatment of bacterial infections. Tigecycline is a new glycyclcycline antimicrobial recently approved for use in the USA, Europe and elsewhere. While related to the tetracyclines, tigecycline overcomes many of the mechanisms responsible for resistance to this class. It is a novel broad spectrum glycylcycline with good activity against Gram-positive, many Gram-negative, anaerobic, and some atypical pathogens that has been developed to address this need. It is efficacious in complicated skin and soft tissue infections and in intra-abdominal infections. This review aims to summarise the key clinical data of daptomycin and tigecycline which hold promise for widespread clinical use in the next decade.     

抗生素后效应与临床用药决策

目的：介绍抗生素的后效应对临床用药决策的指导作用,以促进抗生素的合理应用。方法：参考国内外的有关文献,结合临床用药实际,从抗菌药物的抗生素后效应的长短论证其给药方案。结果：提示药物在低于最低有效浓度时,仍可抑制细菌生长,使药物的有效性得以延长。临床可根据各类抗生素的后效应来确定新的用药剂量、间隔时间和次数,优化给药方案。结论：根据抗生素的后效应制定的给药方案,既可降低药物的毒副作用和医疗费用,又可提高抗菌药物的治疗水平。     

Fengycin--a novel antifungal lipopeptide antibiotic produced by Bacillus subtilis F-29-3

Fengycin is an antifungal lipopeptide complex produced by Bacillus subtilis strain F-29-3. It inhibits filamentous fungi but is ineffective against yeast and bacteria. The inhibition is antagonized by sterols, phospholipids and oleic acid, whereas two other unsaturated fatty acids increase the antifungal effect. Fengycin consists of two main components differing by one amino acid exchange. Fengycin A is composed of 1 D-Ala, 1 L-Ile, 1 L-Pro, 1 D-allo-Thr, 3 L-Glx, 1 D-Tyr, 1 L-Tyr, 1 D-Orn, whereas in fengycin B the D-Ala is replaced by D-Val. The lipid moiety of both analogs is more variable, as fatty acids have been identified as anteiso-pentadecanoic acid (ai-C15), iso-hexadecanoic acid (i-C16), n-hexadecanoic acid (n-C16), and there is evidence for further saturated and unsaturated residues up to C18.