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PubMed2004

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.

Daptomycin↗
PubMed1998

Modulation of phospholipase A2 activity by aminoglycosides and daptomycin: a Fourier transform infrared spectroscopic study.

The antibiotics known as aminoglycosides are commonly used to treat severe infections caused by Gram-negative bacteria. Unfortunately, they often lead to acute renal failure after their accumulation in the lysosomes of renal cells, where an inhibition of the phospholipid catabolism is observed. The lipopeptidic antibiotic daptomycin has been shown to reduce the nephrotoxicity of aminoglycosides, but the exact mechanism of this protection is still unknown. In the present study, Fourier transform infrared spectroscopy (FTIR) has been used to monitor the hydrolysis of phosphatidylcholine by phospholipase A2 (PLA2) from Naja mocambique mocambique venom in the presence of various aminoglycosides and/or daptomycin. Gentamicin and amikacin inhibited the reaction in its early stage. Kanamycin A, tobramycin, and especially kanamycin B enhanced the initial enzyme activity by reducing the lag time. After the initiation period, the reaction proceeded at a much slower rate in the presence of gentamicin. On the other hand, daptomycin led to dramatic alterations of the hydrolysis profile: the initial latency period was eliminated, and the maximal extent of hydrolysis was reduced. When both daptomycin and any of the aminoglycosides were present, the latency period also disappeared, and the phospholipase activity was higher than with the lipopeptide alone. The most drastic change occurred with gentamicin, which was the most inhibitory aminoglycoside when used alone but worked synergistically with daptomycin to yield the most dramatic activation of PLA2.

Aminoglycosides↗
PubMed2006

Combinatorial biosynthesis of novel antibiotics related to daptomycin.

Daptomycin, a cyclic lipopeptide produced by Streptomyces roseosporus, is the active ingredient of Cubicin (daptomycin-for-injection), a first-in-class antibiotic approved for treatment of skin and skin-structure infections caused by Gram-positive pathogens and bacteremia and endocarditis caused by Staphylococcus aureus, including methicillin-resistant strains. Genetic engineering of the nonribosomal peptide synthetase (NRPS) in the daptomycin biosynthetic pathway was exploited for the biosynthesis of novel active antibiotics. lambda-Red-mediated recombination was used to exchange single or multiple modules in the DptBC subunit of the NRPS to modify the daptomycin cyclic peptide core. We combined module exchanges, NRPS subunit exchanges, inactivation of the tailoring enzyme glutamic acid 3-methyltransferase, and natural variations of the lipid tail to generate a library of novel lipopeptides, some of which were as active as daptomycin against Gram-positive bacteria. One compound was more potent against an Escherichia coli imp mutant that has increased outer membrane permeability. This study established a robust combinatorial biosynthesis platform to produce novel peptide antibiotics in sufficient quantities for antimicrobial screening and drug development.

Amino Acid Sequence↗
PubMed2001

Evaluation of daptomycin susceptibility testing by Etest and the effect of different batches of media.

One hundred and ninety-five Gram-positive bacteria representing 17 species were tested for susceptibility to daptomycin by broth microdilution and Etest methods. The geometric mean daptomycin MIC was 0.46 mg/L by broth microdilution tests and 0.73 mg/L by Etest. The concentration of calcium in 12 different batches of agar varied from 4 to 36 mg/L. Daptomycin Etest MICs varied inversely with the calcium concentration. Etest daptomycin MICs for quality control strains were within proposed quality control range on media with >20 mg/L of calcium. Monitoring the calcium levels of agar media by testing appropriate quality control strains is important for daptomycin Etests.

Anti-Bacterial Agents↗
PubMed2002

In vitro bactericidal activity of daptomycin against staphylococci.

MICs and minimum bactericidal concentrations (MBCs) of daptomycin, vancomycin, linezolid and quinupristin-dalfopristin (Q-D) were determined for 108 staphylococcal isolates. All strains were susceptible (MICs) to daptomycin (< or =2.0 mg/L) and Q-D (< or =1.0 mg/L). All but three isolates were susceptible to vancomycin (< or =4.0 mg/L) and all but one methicillin-resistant Staphylococcus aureus strain were susceptible to linezolid (< or =4.0 mg/L). Q-D had the lowest geometric mean MIC (0.29 mg/L) and daptomycin had the lowest geometric mean MBC (0.57 mg/L). Time-kill tests were performed on 25 isolates. Bactericidal activity (>99.9% kill) was observed with daptomycin at 2 mg/L and at 2 x MBC for 92% of strains tested. In comparison, the bactericidal rates for the other drugs at breakpoint concentrations and at 2 x MBC were 72% and 70% for vancomycin, 46% and 60% for Q-D, and 7% and 14% for linezolid. Of the four drugs tested, daptomycin was bactericidal against the most strains and had the most rapid cidal activity.

Acetamides↗
PubMed2004

Influence of protein binding under controlled conditions on the bactericidal activity of daptomycin in an in vitro pharmacodynamic model.

OBJECTIVE: Daptomycin exhibits bactericidal activity against clinically significant Gram-positive bacteria despite being highly bound to human proteins. Evaluations characterizing the effect of protein on daptomycin pharmacodynamics are warranted. METHODS: We utilized an in vitro pharmacodynamic model to simulate daptomycin regimens of 6 mg/kg/day under controlled conditions of pH, calcium and/or protein. Free concentrations were simulated in broth, whereas total concentrations were simulated in broth supplemented with human albumin. Bacterial density was profiled over 48 h for two methicillin-resistant Staphylococcus aureus (MRSA) and two vancomycin-resistant Enterococcus faecium (VREF) clinical isolates. RESULTS: Daptomycin exhibited bactericidal activity against both MRSA isolates, with time to 99.9% killing occurring at 0.5 h and 8 h in broth and in albumin-supplemented broth, respectively. Initial kill was observed against both VREF isolates followed by regrowth. There was no statistical difference (P>0.05) in extent of bacterial kill at 24 or 48 h between the different media. CONCLUSIONS: Although delayed, the extent of kill for daptomycin was unaltered against all isolates in albumin-supplemented broth. Further antimicrobial studies that incorporate protein are warranted to assess the influence of protein in the pharmacodynamic evaluation of antimicrobials.

Anti-Bacterial Agents↗
PubMed2005

Daptomycin tested against 915 bloodstream isolates of viridans group streptococci (eight species) and Streptococcus bovis.

OBJECTIVES: To evaluate the activity of daptomycin tested against numerous species of viridans group streptococci and Streptococcus bovis, which are associated with wound infections, sepsis, cellulitis, endocarditis, abscesses and dental caries. The incidence of penicillin-resistant (non-susceptible) and MLS(B)-resistant strains among viridans group streptococci often varies by species. METHODS: The activity of daptomycin was compared with seven other antimicrobial classes using reference broth microdilution and disc diffusion methods tested against 915 bacteraemic isolates of streptococci (815 viridans group strains; 100 S. bovis). RESULTS: Among all species of viridans group streptococci and S. bovis, 99.9% of isolates were susceptible to daptomycin (MIC values, < or = 0.016-2 mg/L). In contrast, penicillin, erythromycin and tetracycline susceptibility varied widely between species. Erythromycin susceptibility was in the range 48.6-88.7%, penicillin susceptibility in the range 65.5-98.1% and tetracycline in the range 35.0-93.9%. The inter-method agreement between daptomycin and linezolid resistance (comparison agent) disc diffusion and broth microdilution test results was high, each showing near complete susceptibility (99.9%). CONCLUSIONS: Daptomycin is an active antimicrobial agent that has a usable potency against eight species of viridans group streptococci, as well as S. bovis, with all MIC values at < or =2 mg/L.

Anti-Bacterial Agents↗
PubMed2006

Complementation of daptomycin dptA and dptD deletion mutations in trans and production of hybrid lipopeptide antibiotics.

Daptomycin is a lipopeptide antibiotic produced by Streptomyces roseosporus and recently commercialized as Cubicin (daptomycin-for-injection) for treatment of skin and skin-structure infections caused by Gram-positive pathogens. Daptomycin is synthesized by a non-ribosomal peptide synthetase (NRPS) encoded by three overlapping genes, dptA, dptBC and dptD. The dptE and dptF genes, immediately upstream of dptA, are likely to be involved in the initiation of daptomycin biosynthesis by coupling decanoic acid to the N-terminal Trp. Analysis of RT-PCR data suggests that dptE, dptF, dptA, dptBC, dptD and possibly other dpt genes are transcribed as one large message; however, it has been demonstrated that sequential translation of these genes from a long transcript is not essential for robust daptomycin production. The dptA and the dptD genes were deleted from the dpt gene cluster, and expressed from ectopic positions in the chromosome under the control of the strong constitutive ermEp* promoter to produce high levels of lipopeptides. This three-locus trans-complementation system was used to produce hybrid lipopeptide antibiotics by introducing the heterologous lptD and cdaPS3 genes from Streptomyces fradiae and Streptomyces coelicolor, respectively, to complement the DeltadptD mutation.

Anti-Bacterial Agents↗
PubMed2006

Daptomycin: first in a new class of antibiotics for complicated skin and soft-tissue infections.

With increasing antibiotic resistance reported worldwide, there is an urgent need for novel treatments for infections caused by Gram-positive bacteria. Daptomycin is the first in a new class of antibiotic, the cyclic lipopeptides, with activity against a range of Gram-positive pathogens. US approval of daptomycin for the treatment of complicated skin and soft-tissue infections (cSSTIs) caused by Gram-positive bacteria was gained in 2003, with European approval granted in January 2006. Most Gram-positive clinical isolates tested have proved susceptible to daptomycin, including methicillin- and vancomycin-resistant strains. Daptomycin has a novel mode of action, is rapidly bactericidal in vitro and has a low potential for the development of resistance. Two pivotal phase III studies, in a total of 1092 patients with cSSTIs, demonstrated non-inferiority to currently used antibiotics and a comparable tolerability profile. The unique mode of action of daptomycin is described alongside studies demonstrating its potential in the treatment of cSSTIs and other infections caused by Gram-positive bacteria.

Anti-Bacterial Agents↗
PubMed2007

Activity of daptomycin alone and in combination with rifampin and gentamicin against Staphylococcus aureus assessed by time-kill methodology.

The synergistic effects of daptomycin plus gentamicin or rifampin were tested against 50 Staphylococcus aureus strains, with daptomycin MICs ranging between 0.25 and 8 microg/ml. Daptomycin sub-MICs combined with gentamicin concentrations lower than the MIC yielded synergy in 34 (68%) of the 50 strains. Daptomycin combined with rifampin yielded synergy in one vancomycin-intermediate S. aureus strain only, and virtually all synergy occurred between daptomycin and gentamicin.

Anti-Bacterial Agents↗
PubMed1989

Comparative evaluation of daptomycin (LY146032) and vancomycin in the treatment of experimental methicillin-resistant Staphylococcus aureus osteomyelitis in rabbits.

A rabbit model for methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis was used to compare treatment with daptomycin, a new peptolide, and vancomycin. Daptomycin (4 mg/kg) and vancomycin (40 mg/kg) were injected subcutaneously every 12 and 6 h, respectively. After treatment, MRSA was found in bone cultures from 18 of 18 control rabbits, 10 of 17 animals treated with daptomycin, and 11 of 18 animals treated with vancomycin. Drug concentrations were measured in serum, uninfected bone, and infected bone 1 h after daptomycin or vancomycin was injected in a group of rabbits that had been infected for 3 to 4 weeks. Vancomycin was present at the highest concentrations in infected and uninfected bone. The results of this study suggest that daptomycin was similar to vancomycin in the eradication of MRSA from infected bone in an experimental model of osteomyelitis.

Animals↗
PubMed1989

In vitro postantibiotic effect of daptomycin (LY146032) against Enterococcus faecalis and methicillin-susceptible and methicillin-resistant Staphylococcus aureus strains.

The suppression of bacterial growth that persists after brief exposure to antimicrobial agents has been termed the postantibiotic effect (PAE). This pharmacodynamic interaction varies for each microorganism-antimicrobial agent combination. Daptomycin (LY146032) is a new lipopeptide antibiotic with activity against gram-positive organisms. We studied the in vitro bactericidal activities and PAEs of the following drugs: daptomycin compared with penicillin G and vancomycin, without and with gentamicin against Enterococcus faecalis strains; daptomycin compared with nafcillin and vancomycin against methicillin-susceptible Staphylococcus aureus strains; and daptomycin compared with vancomycin against methicillin-resistant S. aureus strains. Daptomycin, alone and when used in combination with gentamicin, exhibited greater bactericidal activity and in general produced a longer PAE than standard effective regimens against the organism strains studied.

Anti-Bacterial Agents↗
PubMed1994

Role of tolerance in treatment and prophylaxis of experimental Staphylococcus aureus endocarditis with vancomycin, teicoplanin, and daptomycin.

The role of Staphylococcus aureus tolerance in the treatment and prophylaxis of endocarditis in rats was investigated. The efficacies of vancomycin, teicoplanin, and daptomycin, alone and in combination with rifampin, were compared in rats with endocarditis infected with a tolerant strain of S. aureus and in rats with endocarditis infected with its nontolerant variant. In vitro the cloxacillin-tolerant strain was also tolerant to vancomycin and teicoplanin, but not to daptomycin. However, tolerance to these antibiotics did not influence the results of treatment of experimental S. aureus endocarditis. There was no difference in the bacterial densities in the vegetations of rats infected with either the tolerant or the nontolerant strain after 5 days of treatment with any of the antibiotic regimens. Of all antibiotics, daptomycin was the most effective in reducing bacterial numbers in vegetations. Combination of rifampin with vancomycin or teicoplanin improved the results of treatment for the tolerant as well as the nontolerant strains. Daptomycin was as effective alone as in combination with rifampin. In contrast, tolerance influenced the prophylactic effects of vancomycin and teicoplanin. The proportion of rats with sterile vegetations after prophylaxis with vancomycin or teicoplanin at a low dose was lower for those infected with the tolerant strain than for those infected with the nontolerant strain. A low dose of daptomycin was equally effective against the tolerant and the nontolerant strains. However, higher doses of all three antibiotics afforded almost full protection against both strains.

Animals↗
PubMed2000

Comparative In vitro activities of daptomycin and vancomycin against resistant gram-positive pathogens.

The in vitro activity of daptomycin against 224 current gram-positive clinical isolates including vancomycin-resistant Enterococcus faecium (VREF), methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus spp. (MRSS), and penicillin-resistant Streptococcus pneumoniae (PRSP) was evaluated. The MICs at which 90% of isolates are inhibited for daptomycin and vancomycin, respectively, were as follows: MRSA, 1 and 2 microg/ml; MRSS, 1 and 4 microg/ml; PRSP, 1 and 0.5 microg/ml; and VREF, 2 and >64 microg/ml. Daptomycin was bactericidal against 82% of 17 VREF isolates. The antibacterial activity of daptomycin was strongly dependent on the calcium concentration of the medium. Daptomycin was active against all gram-positive cocci tested.

Colony Count, Microbial↗
PubMed2001

Pharmacodynamics of daptomycin in a murine thigh model of Staphylococcus aureus infection.

Daptomycin is a lipopeptide antibiotic with activity against gram-positive bacteria, including Staphylococcus aureus. We defined the pharmacodynamic parameters that determine the activity of daptomycin for S. aureus using in vitro methods and the Craig (W. A. Craig, J. Redington, and S. C. Ebert, J. Antimicrob. Chemother. 27[Suppl. C]:29--40, 1991) neutropenic mouse thigh infection model. In Mueller-Hinton broth, the MICs for three S. aureus isolates were 0.1 to 0.2 microg/ml. In mouse serum, the MICs were 1.0 microg/ml. The protein binding of daptomycin was 90 to 92.5% in mouse serum. Single-dose intraperitoneal (i.p.) pharmacokinetic studies with infected mice showed a linear relationship between dose versus the maximum concentration of drug in serum and dose versus the area under the concentration-time curve (AUC). The serum half-life of daptomycin in infected mice was approximately 1.8 h. In single-dose, dose-ranging studies using mice, daptomycin showed a dose-response effect described by an inhibitory sigmoid E(max) (maximum effect) curve (r = 0.974; P << 0.001). The density of S. aureus in untreated controls was 8.26 log(10) CFU/g, and the E(max) was 3.97 log(10) CFU/g. The 50% effective dose (ED(50)) was 3.7 mg/kg of body weight i.p. and the stasis dose was 7.1 mg/kg. Dose fractionation studies at schedules of Q6h, Q12h, and Q24h, for total 24-h ED(30), ED(60), and ED(80) doses of 2.5, 5.6, and 15 mg/kg i.p., showed no difference in effect at each total 24-h dose level by schedule, indicating that the AUC/MIC ratio is the dynamically linked variable.

Animals↗
PubMed2001

Resistance studies with daptomycin.

We studied the in vitro emergence of resistance to daptomycin using three methods: spontaneous resistance incidence, serial passage in the presence of increasing drug concentrations, and chemical mutagenesis. No spontaneously resistant mutants were obtained for any organism tested (<10(-10) for Staphylococcus aureus, <10(-9) for Staphylococcus epidermidis, <10(-9) for Enterococcus faecalis, <10(-9) for Enterococcus faecium, <10(-8) for Streptococcus pneumoniae). Population analysis demonstrated that bacterial susceptibility to daptomycin is heterogeneous. Assay results were sensitive to calcium concentration and culture density, both of which can affect apparent resistance rates. Stable S. aureus mutants were isolated by both serial passage in liquid media and chemical mutagenesis. The daptomycin MICs for these isolates were 8- to 32-fold higher than for the parental strain. Many mutants with high MICs (>12.5 microg/ml) had significant growth defects but did not display phenotypes typical of S. aureus small colony variants. The voltage component (Delta psi) of the bacterial membrane potential was increased in three independent resistant isolates. In vivo data showed that some daptomycin-resistant mutants had lost significant virulence. For other mutants, the degree of in vitro resistance was greater than the change in in vivo susceptibility. These results suggest that infection with some daptomycin-resistant organisms may still be easily treatable.

Animals↗
PubMed2001

In vitro activities of daptomycin against 2,789 clinical isolates from 11 North American medical centers.

The in vitro activity of daptomycin is affected by the concentration of calcium cations in the test medium. Mueller-Hinton broth is currently adjusted to contain 10 to 12.5 mg of magnesium per liter and 20 to 25 mg of calcium per liter, but for testing of daptomycin, greater concentrations of calcium (50 mg/liter) are recommended to better resemble the normal concentration of ionized calcium in human serum. Two levels of calcium were used for broth microdilution tests of 2,789 recent clinical isolates of gram-positive bacterial pathogens. MICs of daptomycin were two- to fourfold lower when the broth contained additional calcium. For most species, however, the percentages of strains that were inhibited by 2.0 microg of daptomycin per ml were essentially identical with the two broth media. Enterococci were the important exception; i.e., 92% were inhibited when tested in calcium-supplemented broth but only 35% were inhibited by 2.0 microg/ml without the additional calcium. This type of information should be considered when selecting criteria for defining in vitro susceptibility to daptomycin.

Anti-Bacterial Agents↗
PubMed2003

Daptomycin dose-effect relationship against resistant gram-positive organisms.

Daptomycin exhibits in vitro bactericidal activity against clinically significant gram-positive bacteria. We employed pharmacodynamic modeling to determine a once-daily dosing regimen of daptomycin that correlates to pharmacodynamic endpoints for different resistant gram-positive clinical strains. An in vitro pharmacodynamic model with an initial inoculum of 6 log(10) CFU/ml was used to simulate daptomycin regimens ranging in dose from 0 to 9 mg/kg of body weight/day, with corresponding exposures reflecting free-daptomycin concentrations in serum. Bacterial density was profiled over 48 h for two methicillin-resistant Staphylococcus aureus (MRSA-67 and -R515), two glycopeptide intermediate-resistant S. aureus (GISA-992 and -147398), and two vancomycin-resistant Enterococcus faecium (VREF-12366 and -SF12047) strains. A sigmoid dose-response model was used to estimate the effective dose required to achieve 50% (ED(50)) and 80% (ED(80)) bacterial density reduction at 48 h. Daptomycin MICs for study isolates ranged from 0.125 to 4 micro g/ml. Model fitting resulted in an r(2) of >0.80 for all tested isolates. Control growths at 48 h ranged from 7.3 to 8.5 log(10) CFU/ml. Sigmoid relationships were not superimposable between categorical resistant species: ED(50) and ED(80) values were 1.9 and 3.1, 4.2 and 5.6, and 5.4 and 6.8 mg/kg for MRSA, GISA, and VREF isolates, respectively. Doses required to achieve ED(50) and ED(80) values correlated with MIC differences between tested organisms. Corresponding area under the concentration-time curve from 0 to 24 h/MIC exposure ratios demonstrated a wide range of ED(80) values among the tested isolates. Doses ranging between 3 and 7 mg/kg produced significant bactericidal activity (ED(80)) against these multidrug-resistant S. aureus and E. faecium isolates.

Animals↗