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PubMed2006

In vitro activities of ceftobiprole, tigecycline, daptomycin, and 19 other antimicrobials against methicillin-resistant Staphylococcus aureus strains from a national survey of Belgian hospitals.

The in vitro activities of 22 antimicrobial agents, including ceftobiprole, daptomycin, and tigecycline, against 511 methicillin-resistant Staphylococcus aureus (MRSA) isolates from 112 Belgian hospitals were studied by using the CLSI agar dilution method. Isolates were characterized by pulsed-field gel electrophoresis (PFGE) analysis and by PCR detection of determinants of resistance to aminoglycosides, macrolides-lincosamides-streptogramins, and tetracyclines. A representative set of isolates with different PFGE genotypes was further characterized by multilocus sequence typing, determination of staphylococcal cassette chromosome mec (SCCmec) type, and multiplex PCR for toxic shock syndrome type 1 (TSST-1) and Panton-Valentine leukocidin genes. MRSA isolates belonged to nine epidemic MRSA clones, of which sequence type 45 (ST45)-SCCmec IV and ST8-SCCmec IV were predominant, accounting for 49 and 20% of isolates, respectively. The distribution of antimicrobial resistance and TSST-1 genes was strongly linked to clonal types. Ceftobiprole, daptomycin, and tigecycline showed high activity against all isolates of these sporadic and epidemic MRSA clones, as indicated by MIC(90)s of 2 mg/liter, 0.5 mg/liter, and 0.25 mg/liter, respectively. The MIC distribution of daptomycin and tigecycline was not different in isolates with decreased susceptibility to glycopeptides or tetracyclines, respectively. Ceftobiprole MICs were not correlated with oxacillin and cefoxitin MICs. These data indicate excellent activity of the newly developed agents ceftobiprole, daptomycin, and tigecycline against MRSA isolates recently recovered from hospitalized patients in Belgium, supporting their therapeutic potential for nosocomial MRSA infections.

Anti-Bacterial Agents↗
PubMed1992

Pharmacokinetics and bactericidal rates of daptomycin and vancomycin in intravenous drug abusers being treated for gram-positive endocarditis and bacteremia.

The pharmacokinetics and bactericidal killing rates (BR) of daptomycin (D) and vancomycin (V) in 12 intravenous drug abusers (6 treated with daptomycin and 6 treated with vancomycin) were evaluated. Pharmacokinetic parameters were determined from multiple serum samples drawn at steady state over a 12-h dosing interval after intravenous infusions of 3 mg of D per kg of body weight and 1,000 mg of V. The BRs were determined from the 1- and 6-h serum samples by using four isolates of Staphylococcus aureus (three methicillin susceptible and one methicillin resistant) obtained from the patients enrolled in the study. Peak serum daptomycin concentrations were lower and volumes of distribution were higher than reported in healthy volunteers. Although not statistically different, D clearance was 22% higher than reported in healthy volunteers. V pharmacokinetics were similar to those reported in previous studies. Daptomycin's BRs, although comparable to those of V in patients' serum, were significantly decreased compared with those found in broth. This may be related to the high degree of protein binding of D (93% versus 50% for V). Conversely, the BRs of V in serum were significantly greater than those in broth. The BRs of D and V in broth were greater when killing curves were performed with test strains in logarithmic versus stationary-phase growth. The ability to kill organisms in stationary phase may be an important factor in determining the performance of an antibiotic in deep-seated infections such as endocarditis.3+

Adult↗
PubMed2000

Once-daily dosing in dogs optimizes daptomycin safety.

Daptomycin is a novel lipopeptide antibiotic with potent bactericidal activity against most clinically important gram-positive bacteria, including resistant strains. Daptomycin has been shown to have an effect on skeletal muscle. To guide the clinical dosing regimen with the potential for the least effect on skeletal muscle, two studies were conducted with dogs to compare the effects of repeated intravenous administration every 24 h versus every 8 h for 20 days. The data suggest that skeletal-muscle effects were more closely related to the dosing interval than to either the maximum concentration of the drug in plasma or the area under the concentration-time curve. Both increases in serum creatine phosphokinase activity and the incidence of myopathy observed at 25 mg/kg of body weight every 8 h were greater than those observed at 75 mg/kg every 24 h despite the lower maximum concentration of drug in plasma. Similarly, the effects observed at 25 mg/kg every 8 h were greater than those observed at 75 mg/kg every 24 h at approximately the same area under the concentration-time curve from 0 to 24 h. Once-daily administration appeared to minimize the potential for daptomycin-related skeletal-muscle effects, possibly by allowing for more time between doses for repair of subclinical effects. Thus, these studies with dogs suggest that once-daily dosing of daptomycin in humans should have the potential to minimize skeletal-muscle effects. In fact, interim results of ongoing clinical trials, which have focused on once-daily dosing, appear to be consistent with this conclusion.

Animals↗
PubMed2000

In vitro activities of daptomycin, vancomycin, linezolid, and quinupristin-dalfopristin against Staphylococci and Enterococci, including vancomycin- intermediate and -resistant strains.

The in vitro activity of daptomycin was compared with those of vancomycin, linezolid, and quinupristin-dalfopristin against a variety (n = 203) of gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and S. epidermidis (MRSA and MRSE, respectively), vancomycin-resistant enterococci (VRE), and vancomycin-intermediate S. aureus (VISA). Overall, daptomycin was more active against all organisms tested, except Enterococcus faecium and VISA, against which its activity was similar to that of quinupristin-dalfopristin. In time-kill studies with MRSA, MRSE, VRE, and VISA, daptomycin demonstrated greater bactericidal activity than all other drugs tested, killing > or =3 log CFU/ml by 8 h. Daptomycin may be a potential alternative drug therapy for multidrug-resistant gram-positive organisms and warrants further investigation.

Acetamides↗
PubMed2003

Increased killing of staphylococci and streptococci by daptomycin compared with cefazolin and vancomycin in an in vitro peritoneal dialysate model.

Peritoneal dialysate fluid (PDF) is a bacteriostatic medium that compromises the antibacterial activity of cell wall-active agents. By use of an in vitro static model, methicillin-resistant Staphylococcus aureus (MRSA), methicillin-susceptible S. aureus (MSSA), methicillin-susceptible Staphylococcus epidermidis (MSSE), and Streptococcus sanguis were exposed to daptomycin at concentrations of 10, 30, and 100 mg/liter, cefazolin at 125 mg/liter, and vancomycin at 25 mg/liter in cation-adjusted Mueller-Hinton Broth or Todd Hewitt Broth (for S. sanguis) and PDF at pHs of 5.5 and 7.4. The pH had no effect on antibacterial activity. Neither cefazolin nor vancomycin produced a bactericidal or a bacteriostatic effect versus MRSA, MSSA, MSSE, or S. sanguis in PDF, while all concentrations of daptomycin were bactericidal against all organisms in PDF. Daptomycin did not exhibit concentration-dependent activity in PDF. Daptomycin appears to be a promising agent for use in peritoneal dialysis-associated peritonitis, producing bacterial kill to a greater extent and at a higher rate than cefazolin or vancomycin in PDF.

Anti-Bacterial Agents↗
PubMed2003

In vitro bactericidal activities of daptomycin against Staphylococcus aureus and Enterococcus faecalis are not mediated by inhibition of lipoteichoic acid biosynthesis.

Previous studies have suggested that lipoteichoic acid biosynthesis inhibition is the mechanism of action of daptomycin. In this investigation, daptomycin inhibited all macromolecular synthesis in Staphylococcus aureus, Enterococcus faecalis, and Enterococcus hirae without kinetic or dose specificity for lipoteichoic acid. Daptomycin remained bactericidal in the absence of ongoing lipoteichoic acid synthesis. Inhibition of lipoteichoic acid synthesis is apparently not the mechanism of action of daptomycin in these pathogens.

Anti-Bacterial Agents↗
PubMed2004

Daptomycin is highly efficacious against penicillin-resistant and penicillin- and quinolone-resistant pneumococci in experimental meningitis.

The penetration of daptomycin, a new lipopeptide antibiotic, into inflamed meninges ranged between 4.37 and 7.53% (mean, 5.97%). Daptomycin was very efficacious in the treatment of experimental pneumococcal meningitis, producing a decrease of -1.20 +/- 0.32 Deltalog(10) CFU/ml. h in the bacterial titer of Streptococcus pneumoniae against a penicillin-resistant strain and of -0.97 +/- 0.32 Deltalog(10) CFU/ml. h against a penicillin- and quinolone-resistant strain found in cerebrospinal fluid (CSF). For both strains, daptomycin was significantly superior to the standard regimen of a combination of ceftriaxone with vancomycin, sterilizing 9 of 10 CSF samples after 4 h. In vitro, daptomycin produced highly bactericidal activity in concentrations above the MIC.

Animals↗
PubMed2004

Population pharmacokinetics of daptomycin.

Data from subjects in nine phase 1 (n = 153) and six phase 2/3 (n = 129) clinical trials were combined to identify factors contributing to interindividual variability in daptomycin pharmacokinetics (PK). Over 30 covariates were considered. A two-compartment model with first-order elimination provided the best fit for data on daptomycin concentrations in plasma over time. In the final population PK model, daptomycin plasma clearance (CL) was a function of renal function, body temperature, and sex. Of these factors, renal function contributed most significantly to interindividual variability. CL varied linearly with the estimated creatinine clearance. CL among dialysis subjects was approximately one-third that of healthy subjects (0.27 versus 0.81 liter/h). CL in females was 80% that in males; however, in clinical trials, the outcome was not affected by sex and therefore this effect is not considered clinically meaningful. The relationship with body temperature should be interpreted cautiously since the analysis included only a limited number of subjects who were hyperthermic. The volume of distribution of the peripheral compartment (V2) and intercompartmental clearance (Q) were linearly related to body weight. V2 increased approximately twofold in the presence of an acute infection. No factors were identified that significantly impacted V1. This analysis supports the dosing of daptomycin on a milligram-per-kilogram-of-body-weight basis and suggests that modified dosing regimens are indicated for patients with severe renal disease and for those undergoing dialysis.

Adolescent↗
PubMed2006

Treatment failure resulting from resistance of Staphylococcus aureus to daptomycin.

Daptomycin, a new cyclic lipopeptide, was recently approved for the treatment of infections by gram-positive organisms, including infections with methicillin-resistant Staphylococcus aureus (MRSA). A patient infected with infected with MRSA developed resistance to daptomycin after prolonged exposure, which resulted in clinical failure. Clinicians should be aware of the possibility of daptomycin resistance and should consider routine testing for daptomycin susceptibility.

Anti-Bacterial Agents↗
PubMed1990

In vitro activity of daptomycin against 297 staphylococcal isolates.

The in vitro activity of daptomycin against 297 clinical isolates of Staphylococcus aureus and S. epidermidis sensu strictu was compared with the activities of cephalothin, dicloxacillin, tobramycin, and vancomycin. Minimal inhibitory concentrations (MICs) were determined by an agar dilution method. Cephalothin and dicloxacillin showed the highest activity against S. aureus on a weight-for-weight basis, all isolates being inhibited by 0.5 mg/l or less of either agent. Cephalothin was somewhat more active against S. epidermidis than was dicloxacillin. Daptomycin and vancomycin exhibited high and similar activity against both S. aureus and S. epidermidis (MIC90% = 1 and 2 mg/l, respectively). Tobramycin was highly active against S. aureus, but the activity against S. epidermidis was greatly variable (MIC range less than or equal to 0.03 - greater than or equal to 16 mg/l). The activity of daptomycin was markedly influenced by the test medium; the MICs were generally 32 times higher when the isolates were tested on Iso-Sensitest agar than on Mueller-Hinton agar. Supplementation of Iso-Sensitest agar with increasing concentrations of calcium potentiated the activity of daptomycin substantially, the results obtained on Iso-Sensitest agar supplemented with 20 mg Ca2+/l being similar to those obtained on Mueller-Hinton agar.

Anti-Bacterial Agents↗
PubMed2004

Lipopeptides, focusing on daptomycin, for the treatment of Gram-positive infections.

The increasing incidence of serious infections caused by antibiotic-resistant Gram-positive bacteria has led to the development of new spectrum-specific agents. One such agent is Cubicin (daptomycin for injection), the first member of a new class of antibacterials called cyclic lipopeptides. Daptomycin has rapid, concentration-dependent bactericidal activity against most clinically significant Gram-positive pathogens, including vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus, and vancomycin-intermediate and -resistant S. aureus. This cyclic lipopeptide has a unique mechanism of action and exhibits a relatively prolonged concentration-dependent postantibiotic effect in vitro. In September 2003 the US FDA approved daptomycin for the treatment of complicated skin and skin-structure infections. With its once-daily dosing, excellent safety profile and low potential for resistance, daptomycin is a welcome new addition to the armamentarium against Gram-positive infections.

Animals↗
PubMed2006

[Daptomycin--a new antibiotic for the treatment of skin and soft tissue infections].

Daptomycin (Cubicin) is a bactericidal lipopeptide antibiotic that was approved in February 2006 for the European market, including Norway, for the treatment of patients with complicated skin and soft tissue infections caused by Gram-positive cocci. Daptomycin is administered intravenously and eliminated mainly by the kidneys. Dose reduction is therefore necessary in patients with impaired renal function. The drug is active only against Gram-positive cocci. Daptomycin therapy of patients with complicated skin and soft tissue infections caused by Gram-positive cocci, is as effective as standard therapy with intravenous semi-synthetic penicillin or vancomycin. The agent is usually well tolerated, but side effects in skeletal muscles are more prevalent than with semi-synthetic penicillins or vancomycin. To prevent development of daptomycin resistance, the agent should be reserved for the treatment of patients with infections caused by Staphylococcus aureus that are resistant to antibiotics commonly used for the treatment of skin and soft tissue infections, e.g. penicillins or clindamycin.

Anti-Bacterial Agents↗
PubMed1989

[Bactericidal effect of daptomycin (LY 146032) compared with vancomycine and teicoplanin against gram-positive bacteria].

Daptomycin (LY 146032) is a semi-synthetic antibiotic whose structure consists of a cyclic peptide with a lipophilic chain. It inhibits synthesis of the bacterial wall differently than vancomycin and teicoplanin. The bactericidal activity of daptomycin was compared with that of vancomycin and of teicoplanin with regard to 54 Gram positive strains of bacteria: (S. aureus meti S and meti R; S. epidermidis meti S and meti R; E. faecalis, E. faecium, and Corynebacterium group JK). Vancomycin and teicoplanin have the same slow and time-dependent bactericidal activity. The activity of daptomycin is different: rapid and concentration-dependent, similar to that of the aminoglycosides. In the case of the Corynebacteria, however, the activity of daptomycin is comparable to that of vancomycin and of teicoplanin slow and time-dependent.

Anti-Bacterial Agents↗
PubMed2004

Daptomycin: the first approved lipopeptide antimicrobial.

OBJECTIVE: To review the literature concerning the first Food and Drug Administration-approved lipopeptide antimicrobial, daptomycin. DATA SOURCES: A PUBMED search was conducted to identify pertinent English-language journal articles between 1985 and November 2003, and additional references were obtained from the bibliographies of these articles. Abstracts from the Interscience Conference on Antimicrobial Agents and Chemotherapy meetings from 1985 through 2003 also were reviewed. STUDY SELECTION: All studies evaluating any aspect of daptomycin. DATA SYNTHESIS: Daptomycin is a semisynthetic lipopeptide, the first such antimicrobial agent to reach the marketplace. Its mechanism of action differs from that of the related agent vancomycin in that much of its effect is not because of inhibition of peptidoglycan biosynthesis, but instead is a result of alterations in cell-membrane electrical charge and transport. It exhibits a broad spectrum of activity against gram-positive aerobes and anaerobes, including methicillin-, penicillin-, aminoglycoside-, and vancomycin-resistant strains. In subjects with normal renal function, the terminal disposition half-life is about 7 to 10 hours. It is principally eliminated as unchanged drug in the urine. Available clinical trial data demonstrate efficacy in complicated skin and skin-structure infections resulting from susceptible gram-positive pathogens, but not in pneumonia. The principal adverse event of concern, although rare, is myotoxicity, manifested by muscle pain and/or weakness and elevated serum creatine phosphokinase (CPK) concentrations. The approved dosage regimen is 4 mg/kg intravenously over 30 minutes once daily for 7 days to 14 days. Studies are underway evaluating doses of up to 8 mg/kg once daily. CONCLUSIONS: Daptomycin, the first lipopeptide antimicrobial to be marketed, exhibits activity against multiresistant gram-positive pathogens, including linezolid- and quinupristindalfopristin-resistant strains. As such, it is a potentially valuable agent to treat infections resulting from such pathogens. To preserve its utility, it should not be used indiscriminately for infections resulting from pathogens sensitive to other antimicrobials. It is probably best used with restricted access and used only for multiresistant gram-positive pathogens where alternative agents cannot be employed. If used, careful monitoring for the signs and symptoms of myotoxicity, including obtaining weekly serum CPK levels, is mandatory. In addition, bacterial sensitivities to this agent should be prospectively monitored by national antimicrobial surveillance programs like SENTRY, TRUST, and LIBRA.

Journal Article↗
PubMed1989

Comparative in vitro activity of daptomycin (LY146032) and vancomycin against gram-positive cocci determined using a pharmacokinetic model.

The activity of daptomycin (LY146032) and vancomycin was compared for methicillin-sensitive and methicillin-resistant (MRSA) strains of Staphylococcus aureus and for Enterococcus faecalis, using a semi-automated model that allows examination of time-kill curves with diminishing drug concentrations, thus reflecting in vivo pharmacokinetics. Exposure to daptomycin resulted in rapid killing of all strains of staphylococci and Enterococcus faecalis tested. Methicillin-sensitive staphylococcal strains appeared marginally more susceptible than MRSA. By contrast, the activity of vancomycin appeared much reduced. For all strains, greater than 90% kill was not observed within 24 h. Enterococcus faecalis was uniformly less susceptible to both agents than were staphylococci. The results suggest that despite similar values for MICs, the activity of daptomycin against strains of Staphylococcus aureus and Enterococcus faecalis is comparable to and may exceed that of vancomycin, although the significance of such differences is uncertain.

Daptomycin↗
PubMed1988

Turbidimetric response of Staphylococcus aureus and Enterococcus faecalis to daptomycin.

The response to daptomycin of three strains of Staphylococcus aureus (one of which was methicillin-resistant) and a strain of Enterococcus faecalis was investigated by continuous turbidimetric monitoring. Daptomycin caused partial inhibition of bacterial growth at concentrations well below those suppressing growth overnight. The activity of the drug was more than 200-fold greater in the presence of a physiological concentration of calcium (2.5 mmol/l) than in its absence. Variants present in cultures inhibited by daptomycin were shown to exhibit decreased susceptibility to the drug and the susceptibility declined further on repeat exposure; however, there was a slow but incomplete reversion to susceptibility on sequential subculture in drug-free broth. Resistance was difficult to induce when the concentration of calcium in the broth exceeded 2.5 mmol/l.

Anti-Bacterial Agents↗
PubMed1991

Bactericidal activity of daptomycin against vancomycin-resistant Enterococcus faecium in an in vitro pharmacokinetic model.

A dynamic in vitro model was used to determine the killing kinetics of daptomycin against 15 vancomycin-resistant clinical isolates of Enterococcus faecium. Concentration profiles simulating those observed in serum following administration of both low-dose (2 mg/kg) and high-dose (6 mg/kg) daptomycin were bactericidal within 5.5 and 2.8 h, respectively. In contrast, when albumin was added to the growth medium, the corresponding bacterial killing times were slowed to greater than 24 h and 7 h; these results suggest that in the clinical setting, daptomycin dosages of approximately 6 mg/kg are required to achieve bactericidal activity against vancomycin-resistant Enterococcus faecium.

Albumins↗
PubMed2004

Clinical glycopeptide-intermediate staphylococci tested against arbekacin, daptomycin, and tigecycline.

We examined the activity of arbekacin, daptomycin, tigecycline, and vancomycin against various Staphylococci isolates with glycopeptide-intermediate (n = 25) and heterogeneous susceptibilities (n = 22) (GISS and hGISS). The minimum inhibitory concentrations (MIC) of each antimicrobial was evaluated in time-kill experiments by using 4 randomly selected GISS isolates tested at 2 and 4 times their respective MIC. The MIC(90) microg/mL ranges for arbekacin, daptomycin, tigecycline, and vancomycin were 2 (0.25-4), 1 (0.0625-2), 0.5 (0.0625-2), and 8 (4-8), respectively. Time kill at 2 times the MIC demonstrated a mean log(10) colony forming units (CFU)/mL change of -2.98 +/- 0.708, -3.6 +/- 0.509, -2.48 +/- 0.647, and +1.14 +/- 0.1 arbekacin, daptomycin, tigecycline, and vancomycin, respectively. At 4 times the MIC, significant activity for all compounds was noted with a log(10) CFU/mL decrease range from 3.68 to 2.74 +/- 0.66. Overall, all the antimicrobials tested (with the exception of vancomycin) exhibited significant in vitro activity against GISS. These compounds may offer therapeutic options for the treatment of GISS.

Aminoglycosides↗