-
The efficacy and safety of daptomycin vs. vancomycin for the treatment of cellulitis and erysipelas.International Journal of Clinical... Mar 2009Results from previous trials suggest that daptomycin may result in faster clinical improvement than penicillinase-resistant penicillins or vancomycin for patients with... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Results from previous trials suggest that daptomycin may result in faster clinical improvement than penicillinase-resistant penicillins or vancomycin for patients with complicated skin and skin structure infections.
OBJECTIVE
The objective was to evaluate whether daptomycin treatment of cellulitis or erysipelas would result in faster resolution compared with vancomycin.
DESIGN
The study was a prospective, evaluator-blinded, multi-centre trial. Patients were randomised to receive daptomycin 4 mg/kg once daily or vancomycin according to standard of care for 7-14 days.
PATIENTS
Adults diagnosed with cellulitis or erysipelas requiring hospitalisation and intravenous antibiotic therapy were eligible for enrolment.
RESULTS
The clinical success rates were 94.0% for daptomycin and 90.2% for vancomycin (95% confidence interval for the difference, -6.7%, 14.3%). There were no statistically significant differences between treatment arms in the time to resolution or improvement in any of the predefined clinical end-points. Both daptomycin and vancomycin were well tolerated.
CONCLUSIONS
There was no difference in the rate of resolution of cellulitis or erysipelas among patients treated with daptomycin or vancomycin. Daptomycin 4 mg/kg once daily appeared to be effective and safe for treating cellulitis or erysipelas.
Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Cellulitis; Daptomycin; Erysipelas; Female; Humans; Male; Middle Aged; Prospective Studies; Treatment Outcome; Vancomycin; Young Adult
PubMed: 19222623
DOI: 10.1111/j.1742-1241.2008.01988.x -
The Journal of Biological Chemistry Apr 2014Daptomycin is an acidic lipopeptide antibiotic that, in the presence of calcium, forms oligomeric pores on membranes containing phosphatidylglycerol. It is clinically...
Daptomycin is an acidic lipopeptide antibiotic that, in the presence of calcium, forms oligomeric pores on membranes containing phosphatidylglycerol. It is clinically used against various Gram-positive bacteria such as Staphylococcus aureus and Enterococcus species. Genetic studies have indicated that an increased content of cardiolipin in the bacterial membrane may contribute to bacterial resistance against the drug. Here, we used a liposome model to demonstrate that cardiolipin directly inhibits membrane permeabilization by daptomycin. When cardiolipin is added at molar fractions of 10 or 20% to membranes containing phosphatidylglycerol, daptomycin no longer forms pores or translocates to the inner membrane leaflet. Under the same conditions, daptomycin continues to form oligomers; however, these oligomers contain only close to four subunits, which is approximately half as many as observed on membranes without cardiolipin. The collective findings lead us to propose that a daptomycin pore consists of two aligned tetramers in opposite leaflets and that cardiolipin prevents the translocation of tetramers to the inner leaflet, thereby forestalling the formation of complete, octameric pores. Our findings suggest a possible mechanism by which cardiolipin may mediate resistance to daptomycin, and they provide new insights into the action mode of this important antibiotic.
Topics: Anti-Bacterial Agents; Biological Transport; Calorimetry; Cardiolipins; Cell Membrane Permeability; Daptomycin; Gram-Positive Bacteria
PubMed: 24616102
DOI: 10.1074/jbc.M114.554444 -
Antimicrobial Agents and Chemotherapy 2014The effects of prior vancomycin exposure on ceftaroline and daptomycin therapy against methicillin-resistant Staphylococcus aureus (MRSA) have not been widely studied....
The effects of prior vancomycin exposure on ceftaroline and daptomycin therapy against methicillin-resistant Staphylococcus aureus (MRSA) have not been widely studied. Humanized free-drug exposures of vancomycin at 1 g every 12 h (q12h), ceftaroline at 600 mg q12h, and daptomycin at 10 mg/kg of body weight q24h were simulated in a 96-h in vitro pharmacodynamic model against three MRSA isolates, including one heteroresistant vancomycin-intermediate S. aureus (hVISA) isolate and one VISA isolate. A total of five regimens were tested: vancomycin, ceftaroline, and daptomycin alone for the entire 96 h, and then sequential therapy with vancomycin for 48 h followed by ceftaroline or daptomycin for 48 h. Microbiological responses were measured by the changes in log10 CFU during 96 h from baseline. Control isolates grew to 9.16 ± 0.32, 9.13 ± 0.14, and 8.69 ± 0.28 log10 CFU for MRSA, hVISA, and VISA, respectively. Vancomycin initially achieved ≥3 log10 CFU reductions against the MRSA and hVISA isolates, followed by regrowth beginning at 48 h; minimal activity was observed against VISA. The change in 96-h log10 CFU was largest for sequential therapy with vancomycin followed by ceftaroline (-5.22 ± 1.2, P = 0.010 versus ceftaroline) and for sequential therapy with vancomycin followed by ceftaroline (-3.60 ± 0.6, P = 0.037 versus daptomycin), compared with daptomycin (-2.24 ± 1.0), vancomycin (-1.40 ± 1.8), and sequential therapy with vancomycin followed by daptomycin (-1.32 ± 1.0, P > 0.5 for the last three regimens). Prior exposure of vancomycin at 1 g q12h reduced the initial microbiological response of daptomycin, particularly for hVISA and VISA isolates, but did not affect the response of ceftaroline. In the scenario of poor vancomycin response for high-inoculum MRSA infection, a ceftaroline-containing regimen may be preferred.
Topics: Anti-Bacterial Agents; Cephalosporins; Colony Count, Microbial; Daptomycin; Drug Combinations; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Models, Statistical; Vancomycin; Vancomycin Resistance; Ceftaroline
PubMed: 24217694
DOI: 10.1128/AAC.01516-13 -
Antimicrobial Agents and Chemotherapy Aug 2004We previously observed marked synergy between daptomycin and both rifampin and ampicillin against vancomycin-resistant enterococci (VRE). Because the synergy between...
We previously observed marked synergy between daptomycin and both rifampin and ampicillin against vancomycin-resistant enterococci (VRE). Because the synergy between daptomycin and ampicillin was observed for 100% of VRE strains with high-level ampicillin resistance (ampicillin MIC of > or =128 microg/ml), we looked for synergy between daptomycin and other beta-lactams against 18 strains of methicillin-resistant Staphylococcus aureus (MRSA) by employing a time-kill method using Mueller-Hinton broth supplemented to 50 mg of Ca2+/liter. All strains were resistant to oxacillin (16 of 18 strains were resistant at drug concentrations of > or =256 microg/ml), and all strains were susceptible to daptomycin (the MIC at which 90% of the tested isolates were inhibited was 1 microg/ml). Daptomycin was tested at concentrations of 2, 1, 0.5, 0.25, 0.125, and 0.0625 microg/ml alone or in combination with oxacillin at a fixed concentration of 32 microg/ml. Synergy was found for all 18 strains with daptomycin at one-half the MIC in combination with 32 microg of oxacillin/ml, and synergy was found for 11 of 18 strains (61%) with daptomycin at one-fourth the MIC or less in combination with oxacillin. At 24 h, the daptomycin-oxacillin combination with daptomycin at one-half the MIC showed bactericidal activity against all 18 strains, and the combination with one-fourth the daptomycin MIC showed bactericidal activity against 9 of 18 strains. We also used a novel screening method to look for synergy between daptomycin and other beta-lactams. In this approach, daptomycin was incorporated into Ca(2+)-supplemented Mueller-Hinton agar at subinhibitory concentrations, and synergy was screened by comparing test antibiotic Kirby-Bauer disks on agar with and without daptomycin. By this method, daptomycin with ampicillin-sulbactam, ticarcillin-clavulanate, or piperacillin-tazobactam showed synergy comparable to or greater than daptomycin with oxacillin. For seven of the eight strains tested, time-kill studies confirmed synergy between daptomycin and ampicillin-sulbactam with ampicillin in the range of 2 to 8 microg/ml. The combination of daptomycin and beta-lactams may be useful for the treatment of MRSA infection, but further studies are needed to elucidate the mechanisms and to determine the in vivo efficacy of the combination.
Topics: Anti-Bacterial Agents; Daptomycin; Drug Synergism; Methicillin Resistance; Microbial Sensitivity Tests; Oxacillin; Penicillins; Staphylococcus aureus; Time Factors; beta-Lactam Resistance
PubMed: 15273094
DOI: 10.1128/AAC.48.8.2871-2875.2004 -
Journal of Burn Care & Research :... May 2020Previous studies and the concentration-dependent antibacterial actions of daptomycin suggested that a high dose would be needed for difficult-to-treat infections in burn...
Previous studies and the concentration-dependent antibacterial actions of daptomycin suggested that a high dose would be needed for difficult-to-treat infections in burn patients. Here, we evaluated the effects of administration of low and high doses of daptomycin in patients with severe burn injuries. The study retrospectively analyzed 10 patients with severe burn injuries, using pharmacokinetic (PK) and pharmacodynamic (PD) evaluations of daptomycin doses given to combat serious infections. Daptomycin was administered as a single dose or by multiple doses intravenously at a standard dose of 6 mg/kg/d or a high dose of 12 mg/kg/d for 7 to 14 days. The serum concentrations of daptomycin from patients were analyzed by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). Burn injury patients treated with high-dose daptomycin had a linear PK profile and a negative correlation between the AUC0-24 and Baux score (R2 = .953 and R2 = .801). The Cmax, AUC0-24, and t(h)½ increased significantly compared with patients given a standard dose. The efficacy of daptomycin against Staphylococcus aureus showed significantly higher rates of (AUC0-24)/MIC and Cmax/MIC after high-dose daptomycin compared with the standard dose, reflected in a significant correlation between a high dose and the Baux score (r = .976, P < .001). Positive S. aureus cultures from two of three high-dose and none of two daptomycin low-dose patients converted from positive to negative after therapy. No serious adverse events or discontinuation of the drug occurred during the treatment period. Daptomycin doses up to 12 mg/kg/d were well tolerated in Chinese patients with severe burn injuries, which were complicated by infections with S. aureus.
Topics: Adult; Anti-Bacterial Agents; Burns; China; Chromatography, Liquid; Daptomycin; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Retrospective Studies; Staphylococcal Infections; Tandem Mass Spectrometry; Wound Infection
PubMed: 32006005
DOI: 10.1093/jbcr/iraa020 -
The Journal of Antimicrobial... Dec 2021The cyclic anionic lipopeptide daptomycin is used in the treatment of severe infections caused by Gram-positive pathogens, including MRSA. Daptomycin resistance,...
BACKGROUND
The cyclic anionic lipopeptide daptomycin is used in the treatment of severe infections caused by Gram-positive pathogens, including MRSA. Daptomycin resistance, although rare, often results in treatment failure. Paradoxically, in MRSA, daptomycin resistance is usually accompanied by a concomitant decrease in β-lactam resistance in what is known as the 'see-saw effect'. This resensitization is extensively used for the treatment of MRSA infections, by combining daptomycin and a β-lactam antibiotic, such as oxacillin.
OBJECTIVES
We aimed: (i) to investigate the combined effects of daptomycin and oxacillin on the lipid composition of the cellular membrane of both daptomycin-resistant and -susceptible MRSA strains; and (ii) to assess the involvement of the post-translocational protein PrsA, which plays an important role in oxacillin resistance in MRSA, in membrane lipid composition and remodelling during daptomycin resistance/β-lactam sensitization.
RESULTS
The combination of microbiological and biochemical studies, with fluorescence microscopy using lipid probes, showed that the lipid composition and surface charge of the daptomycin-resistant cells exposed to daptomycin/oxacillin were dependent on antibiotic concentration and directly associated with PrsA, which influenced cardiolipin remodelling/relocation.
CONCLUSIONS
Our findings show that PrsA, in addition to its post-transcriptional role in the maturation of PBP 2a, is a key mediator of cell membrane remodelling connected to the see-saw effect and may have a key role in the resensitization of daptomycin-resistant strains to β-lactams, such as oxacillin.
Topics: Anti-Bacterial Agents; Bacterial Proteins; Daptomycin; Lipoproteins; Membrane Lipids; Membrane Proteins; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Oxacillin; beta-Lactams
PubMed: 34618036
DOI: 10.1093/jac/dkab356 -
Antimicrobial Agents and Chemotherapy Jul 2006A total of 207 Staphylococcus aureus strains, including 105 well-characterized strains with decreased susceptibility to vancomycin (17 vancomycin-intermediate S. aureus...
Daptomycin bactericidal activity and correlation between disk and broth microdilution method results in testing of Staphylococcus aureus strains with decreased susceptibility to vancomycin.
A total of 207 Staphylococcus aureus strains, including 105 well-characterized strains with decreased susceptibility to vancomycin (17 vancomycin-intermediate S. aureus [VISA] and 88 heteroresistant VISA [hVISA] strains) and 102 wild-type methicillin-resistant S. aureus (MRSA-WT) strains were tested by reference/standardized broth microdilution and disk diffusion methods, as well as by Etest (AB BIODISK, Solna, Sweden), against daptomycin and vancomycin. The lowest concentration of antimicrobial agent that killed > or = 99.9% of the initial inoculum was defined as the minimum bactericidal concentration (MBC) endpoint, and time-kill curves were performed in selected strains to further evaluate bactericidal activity. All MRSA-WT and hVISA strains were inhibited by < or = 1 microg/ml of daptomycin, while the VISA strains showed slightly higher daptomycin MICs (range, 0.5 to 4 microg/ml). All daptomycin MBC results were at the MIC or twofold higher. In contrast, 14.7% of MRSA-WT, 69.3% of hVISA, and all VISA strains showed a vancomycin MBC/MIC ratio of > or = 32 or an MBC of > or = 16 microg/ml (tolerant). The correlation coefficients between broth microdilution and disk diffusion method results were low for daptomycin (0.07) and vancomycin (0.11). Eight (3.8%) strains (all hVISA or VISA) were "nonsusceptible" to daptomycin by broth microdilution methods but susceptible by the disk diffusion method. For vancomycin, 35 (16.9%) strains were nonsusceptible by broth microdilution methods but susceptible by disk diffusion methods. In conclusion, daptomycin was highly bactericidal against S. aureus strains, and its bactericidal activity was not affected by decreased susceptibility to vancomycin. In contrast, many (one in seven) contemporary MRSA-WT, the majority of hVISA, and all VISA strains showed vancomycin MBC/MIC ratios consistent with tolerance, a predictor of poor clinical response. Disk diffusion tests generally failed to detect strains categorized as nonsusceptible to daptomycin or vancomycin by the reference broth microdilution method or Etest, and reassessment of breakpoints should be immediately attempted for MIC methods suggested as the test of choice.
Topics: Anti-Bacterial Agents; Daptomycin; Humans; Methicillin Resistance; Microbial Sensitivity Tests; Staphylococcus aureus; Vancomycin; Vancomycin Resistance
PubMed: 16801409
DOI: 10.1128/AAC.01491-05 -
Clinical Therapeutics Nov 2004The aims of this article were: to summarize the pharmacology, pharmacokinetics, and efficacy of daptomycin; to explore its safety profile; and to discuss its current and... (Review)
Review
OBJECTIVES
The aims of this article were: to summarize the pharmacology, pharmacokinetics, and efficacy of daptomycin; to explore its safety profile; and to discuss its current and potential roles as an antimicrobial therapy.
METHODS
A literature search was conducted using the MEDLINE (1966-August 2004) and International Pharmaceutical Abstracts (1970-August 2004) databases with the search terms daptomycin, LY146032, and lipopeptide antibiotics. Abstracts of the Interscience Conference on Antimicrobial Agents and Chemotherapy and documents submitted to the US Food and Drug Administration were also reviewed.
RESULTS
Phase III study results suggest no difference in efficacy or tolerability between daptomycin 4 mg/kg IV QD and vancomycin or semisynthetic penicillins for complicated skin and skin-structure infections. Animal studies suggest daptomycin may be useful for the treatment of endocarditis. Daptomycin is not indicated for pneumonia, with poorer outcomes than conventional treatment It is available as an IV medication and exhibits 92% plasma protein binding in vitro. In healthy adult humans, daptomycin has a volume of distribution of 0.1 L/kg and a plasma elimination half-life of approximately 9 hours, and is eliminated primarily by renal excretion (approximately 54%). In patients with reduced renal function, including those receiving hemodialysis and peritoneal dialysis, the dose interval should be 48 hours. No dosage adjustment appears to be necessary for mild to moderate hepatic impairment. The use of daptomycin in patients with severe hepatic impairment has not been assessed. The most commonly reported adverse events include constipation, nausea, injection-site reactions, headache, and diarrhea. Patients should also be monitored regularly for skeletal muscle toxicity.
CONCLUSIONS
Daptomycin may be useful for complicated skin and skin-structure infections and gram-positive pathogens resistant to conventional antimicrobials. However, limited data are currently available for duration of treatment beyond 14 days and at doses >4 mg/kg QD.
Topics: Animals; Anti-Bacterial Agents; Bacteremia; Clinical Trials as Topic; Community-Acquired Infections; Daptomycin; Endocarditis; Humans; Pneumonia, Bacterial; Skin Diseases, Bacterial; Urinary Tract Infections
PubMed: 15639687
DOI: 10.1016/j.clinthera.2004.11.014 -
Biophysical Journal Jul 2017Membrane-active antibiotics are potential alternatives to the resistance-prone conventional antibiotics. Daptomycin, a cyclic lipopeptide, is the only membrane-active...
Membrane-active antibiotics are potential alternatives to the resistance-prone conventional antibiotics. Daptomycin, a cyclic lipopeptide, is the only membrane-active antibiotic approved by the U.S. Food and Drug Administration so far. The drug interacts with the cytoplasmic membranes of Gram-positive pathogens, causing membrane permeabilization to ions and cell death. The antibiotic activity is calcium-ion dependent and correlates with the target membrane's content of phosphatidylglycerol (PG). For such a complex reaction with membranes, it has been difficult to uncover the molecular process that underlies its antibacterial activity. The role of the cofactor, calcium ions, has been confusing. Many have proposed that calcium ions binding to daptomycin is a precondition for membrane interaction. Here, we report our findings on the molecular state of daptomycin before and after its membrane-binding reaction, particularly at therapeutic concentrations in the low micromolar range. We were able to perform small-angle x-ray scattering at sufficiently low daptomycin concentrations to determine that the molecules are monomeric before membrane binding. By careful circular dichroism (CD) analyses of daptomycin with Ca and PG-containing membranes, we found that there are only two states identifiable by CD, one before and another after membrane binding; all other CD spectra are linear combinations of the two. Before membrane binding, the molecular state of daptomycin as defined by CD is the same with or without calcium ions. We are able to determine the stoichiometric ratios of the membrane-binding reaction. The stoichiometric ratio of daptomycin to calcium is 2:3. The stoichiometric ratio of daptomycin to PG is ∼1:1 if only the PG lipids in the outer leaflets of membranes are accessible to daptomycin.
Topics: Anti-Bacterial Agents; Calcium; Cations, Divalent; Circular Dichroism; Daptomycin; Models, Molecular; Phosphatidylcholines; Phosphatidylglycerols; Scattering, Small Angle; Unilamellar Liposomes; X-Ray Diffraction
PubMed: 28700928
DOI: 10.1016/j.bpj.2017.05.025 -
Le Infezioni in Medicina Jun 2015Methicillin-resistant Staphylococcus aureus (MRSA) associated infection has become a worrisome issue worldwide. Glycopeptides are the backbone antibiotics for the... (Review)
Review
Methicillin-resistant Staphylococcus aureus (MRSA) associated infection has become a worrisome issue worldwide. Glycopeptides are the backbone antibiotics for the treatment of MRSA infections. However, several reports have highlighted the limitations of vancomycin. Daptomycin is successfully used for the treatment of serious MRSA infections, however selection of resistant strains has been reported during daptomycin-monotherapy. This review will briefly discuss the available data on daptomycin/beta-lactam combination therapies for the treatment of MRSA infections.
Topics: Anti-Bacterial Agents; Daptomycin; Drug Therapy, Combination; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections; Treatment Outcome; beta-Lactams
PubMed: 26110289
DOI: No ID Found