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PubMed2004

Determination of the pharmacodynamic profile of daptomycin against Streptococcus pneumoniae isolates with varying susceptibility to penicillin in a murine thigh infection model.

BACKGROUND: Daptomycin has demonstrated in vitro activity against gram-positive organisms, including Streptococcus pneumoniae. However, the pharmacodynamic (PD) profile of daptomycin is needed to relate the activity of the drug to biologically achievable concentrations. METHODS: The PD profile of daptomycin against four S. pneumoniae isolates was determined using the immunocompromised murine thigh model. Due to the high protein binding of this agent, PD parameters were calculated based on free drug exposures. Efficacy was assessed by the change in log colony-forming units (CFU) in thighs after 24 h of drug treatment. RESULTS: Daptomycin produced a 7.1 (95% confidence interval 7.0-7.2) log(10) CFU kill. The ratio between overall drug exposure and the minimum inhibitory concentration (MIC) (AUC/MIC) was the most predictive of the PD parameters. The S. pneumoniae AUC/MIC required for static effects was 12 (95% confidence interval 10-14). Eighty percent and 99% of maximal kill was achieved at ratios of 35 (95% confidence interval 32-39) and 184 (95% confidence interval 160-208), respectively. CONCLUSIONS: Clinically achievable serum drug exposures produced by the lowest dose of daptomycin currently studied in humans (4 mg/kg/day) should result in a potent in vivo bactericidal effect against infections due to S. pneumoniae such as bacteremia, where serum drug concentrations adequately reflect the concentration at the site of infection.

Animals↗
PubMed2005

In vitro activity of daptomycin versus linezolid and vancomycin against gram-positive uropathogens and ampicillin against enterococci, causing complicated urinary tract infections.

OBJECTIVES: The existing therapeutic options for complicated urinary tract infections (UTI) caused by gram-positive uropathogens are not always optimal. Therefore, newer antimicrobials have to be assessed. METHODS: The antimicrobial activity of daptomycin was tested versus linezolid, vancomycin, and ampicillin (enterococci on ly), against pathogens from three different collections: (1) Uropathogens from hospitalized urological patients with complicated and/or hospital-acquired UTIs of the Urologic Clinic, Hospital St. Elisabeth, Straubing. (2) Uropathogens from a multicenter study comprising 37 urological centers throughout Germany. (3) Methicillin-resistant Staphylococcus aureus (MRSA) isolates of patients and staff within the Hospital St. Elisabeth, Straubing. Genotyping of the latter isolates was performed by pulsed-field gel electrophoresis. The minimal inhibitory concentrations (MIC) of daptomycin, linezolid, vancomycin, and ampicillin (only tested against enterococci) were determined by an agar dilution method using a multipointer with an inoculum of 10(4) CFU per point. RESULTS: For all methicillin-susceptible Staphylococcus aureus (n = 25), MRSA (n = 49), methicillin-susceptible coagulase-negative staphylococci (n = 129), methicillin-resistant coagulase-negative staphylococci (n = 33), for Enterococcus faecalis (n = 289), and for Enterococcus faecium (n = 4) the MICs ranged up to 2 mg/l (daptomycin, linezolid), up to 4 mg/l (vancomycin), and up to 8 mg/l (ampicillin, enterococci only) indicating that all strains were susceptible to the antibiotics tested. CONCLUSIONS: According to the in vitro activity daptomycin may be considered a promising antibacterial agent for the treatment of complicated UTI caused by gram-positive uropathogens. Thus, daptomycin should be evaluated in a clinical study.

Acetamides↗
PubMed2004

Single-dose pharmacokinetics of daptomycin in young and geriatric volunteers.

Daptomycin is a novel lipoprotein antibiotic that was recently approved for the treatment of complicated skin and skin structure infections caused by aerobic gram-positive bacteria. The pharmacokinetics of daptomycin was evaluated after a single 0.5-hour intravenous infusion of 4 mg/kg to groups of young adult (18-30 years) and geriatric (>or= 75 years) volunteers. Daptomycin was safe and well tolerated. No adverse events related to the infusion were reported. With increased age, there were increases in the area under the plasma concentration-time curve extrapolated to infinity (AUC( infinity )) and the terminal elimination half-life. Systemic (CL) and renal clearance (CL(R)) both decreased with increasing age. The observed changes seen in CL between the two cohorts were most likely a result of changes in renal function, as estimated by creatinine clearance. No statistically significant differences were observed between the two groups in the maximum plasma concentration (C(max)) and volume of distribution at steady state (Vd(ss)). The confidence intervals for the arithmetic mean ratios of the fraction of the dose excreted in the urine as daptomycin (%Fe) (geriatric subjects over younger subjects) were 60% to 101%, indicating that %Fe(dose) was lower in geriatric subjects. These results demonstrate that changes in the pharmacokinetics of daptomycin in the elderly are attributable to changes in renal function, whereas age per se is not a significant factor.

Adolescent↗
PubMed2002

Daptomycin morphostructural damage in Bacillus cereus visualized by atomic force microscopy.

Daptomycin is a novel, rapidly bactericidal in vitro antibiotic that is under investigation for the treatment of serious Gram-positive infections. Although daptomycin appears to disrupt membrane function, the precise mechanism of action has not been fully elucidated. Atomic force microscopy (AFM) is an innovative technique that allows high-resolution visualization and digital image manipulation of cell surface structures in 3 dimensions without the use of photons and electrons. The aim of this study was to use AFM to investigate the morphostructural changes in Bacillus cereus that occur upon daptomycin administration. The effects of daptomycin at 4x and 8x the minimal inhibitory concentration were visualized during an 8-hour incubation period. Atomic force microscopy images showed aberrant bacterial surface formations, including flattening and shrinking of cells and leakage of cytoplasm through the membrane. In addition to structural changes, the destabilization of flagella was also observed. These results support previous data suggesting that daptomycin disrupts membrane function.

Anti-Bacterial Agents↗
PubMed2005

Evaluation of in vitro interaction of daptomycin with gentamicin or beta-lactam antibiotics against Staphylococcus aureus and Enterococci by FIC index and timed-kill curves.

The interactions of daptomycin with gentamicin and 5 beta-lactam agents were determined by checkerboard and timed-kill studies. Eighty isolates were tested by checkerboard: 20 each of methicillin-resistant Staphylococcus aureus (MRSA), methicillin-susceptible Staphylococcus aureus (MSSA), vancomycin-susceptible Enterococcus faecalis (VSEF) and vancomycin-resistant enterococci (VRE). Time kill curves were performed on 8 selected isolates: 2 each of MRSA, MSSA, VSEF and VRE. Checkerboard results showed highest frequency of synergistic effects against VSEF (35-75%) with daptomycin combined with ceftriaxone, cefepime or imipenem; a modest effect with most combinations against VRE and MRSA (5-20%); and indifference with daptomycin and most agents against MSSA (0-5%); except with daptomycin with oxacillin where 10-20% synergy was observed. Synergistic interaction was confirmed by time kill studies in seven of ten isolates where checkerboard suggested synergy. A bactericidal effect was exerted in 5/7 synergistic combinations. The in vitro data suggest that daptomycin combined with other antibiotics may be microbiologically beneficial and not antagonistic.

Anti-Bacterial Agents↗
PubMed2005

Successful treatment of Corynebacterium striatum endocarditis with daptomycin plus rifampin.

OBJECTIVE: To report a case of Corynebacterium striatum endocarditis that was treated successfully with daptomycin plus rifampin following an unsuccessful attempt at vancomycin desensitization and failure of linezolid therapy. CASE SUMMARY: A 46-year-old woman with hemodialysis-dependent chronic renal failure was admitted for a graft-related infection. She presented with C. striatum endocarditis that was treated with daptomycin plus rifampin due to a history of allergies to vancomycin and beta-lactam antibiotics and failure of linezolid therapy. The patient received daptomycin and rifampin for a total of 6 weeks. Three months after completion of treatment, no recurrence of endocarditis was evident. DISCUSSION: Daptomycin is a lipopeptide antibiotic, with rapid bactericidal activity. It has demonstrated efficacy in animal models of staphylococcal, streptococcal, and enterococcal endocarditis. Case reports of its activity in methicillin-resistant Staphylococcus aureus endocarditis have also been documented. CONCLUSIONS: Daptomycin, which has shown in vitro activity against C. striatum, may be a viable treatment option for patients with C. striatum endocarditis who are either allergic or refractory to traditional antibiotics.

Anti-Bacterial Agents↗
PubMed2005

Daptomycin-resistant Enterococcus faecium in a patient with acute myeloid leukemia.

Daptomycin is a lipopeptide antimicrobial used for the treatment of aerobic gram-positive skin and soft tissue infections. We describe a patient with acute myeloid leukemia whose febrile neutropenia was treated with daptomycin and who later developed daptomycin-resistant Enterococcus faecium infection. Defervescence and negative blood cultures ensued after treatment with linezolid. Guidelines for testing daptomycin susceptibillities of enterococci include breakpoints only for vancomycin-susceptible Enterococcus faecalis, making interpretation of minimum inhibitory concentrations for common clinical infections difficult. No enterococcal cross-resistance has been reported among daptomycin, linezolid, or quinupristin-dalfopristin, and these agents may be viable alternatives.

Acute Disease↗
PubMed1989

[Bactericidal activity of daptomycin and vancomycin alone or in combination with tobramycin, netilmicin or ampicillin against enterococcus].

The in vitro bactericidal activity of daptomycin and vancomycin alone or in combination was studied against enterococci in a microtiter checkerboard assay and by kill-kinetic experiments. Daptomycin was more active than vancomycin and was bactericidal. Better Fractional Bactericidal Concentration indices were observed with combinations of vancomycin with aminoglycosides, but in kill-kinetic studies, the combinations of 4 MICs of daptomycin with 4 mg/l of tobramycin or netilmicin produced the more lethal effect; these combinations were even more lethal than ampicillin and aminoglycosides in the same conditions. While vancomycin and ampicillin were antagonistic, synergistic FBC indices were observed with daptomycin and ampicillin in combination, but at 4 MICs of each antibiotic, the combination was less bactericidal than ampicillin alone. The bactericidal effect obtained with daptomycin in combination with aminoglycosides suggest that further evaluation of these combinations in enterococcal endocarditis could have a clinical interest if this bactericidal effect was confirmed by in vivo studies.

Ampicillin↗
PubMed2005

In vitro activity of daptomycin against clinical isolates of Gram-positive bacteria.

We determined the activity of daptomycin, a recently FDA-approved antimicrobial agent, against clinical isolates of Gram-positive bacteria, including viridans group streptococci (16 Streptococcus mitis species group, 12 S. mutans species group, 9 S. anginosus species group, 8 S. sanguinis species group, 5 S. salivarius species group) from patients with infective endocarditis, 32 methicillin-resistant Staphylococcus aureus, 32 high-level penicillin-resistant Streptococcus pneumoniae, 38 vancomycin-resistant enterococci (including 1 linezolid-resistant isolate), and the following unusual Gram-positive bacteria: 3 Listeria monocytogenes, 4 Erysipelothrix rhusiopathiae, 9 Corynebacterium species, 10 Abiotrophia/Granulicatella species, 2 Rothia (Stomatococcus) mucilaginosus, and 4 Gemella morbillorum. Daptomycin minimum inhibitory concentration (MIC)(90) values for the viridans group streptococci, methicillin-resistant S. aureus, penicillin-resistant S. pneumoniae, and Enterococcus species were 0.5, 0.5, < or =0.125, and 4 microg/ml, respectively. The daptomycin MIC range for the unusual Gram-positive bacteria was < or =0.125-2 microg/ml. We conclude that daptomycin has in vitro activity against viridans group streptococci associated with endocarditis as well as against several types of unusual Gram-positive bacteria that can cause endocarditis.

Anti-Bacterial Agents↗
PubMedDate not supplied

The bactericidal activity of ampicillin, daptomycin, and vancomycin against ampicillin-resistant Enterococcus faecium.

Ampicillin, daptomycin, and vancomycin, alone and in combination with gentamicin, were examined for bactericidal effects on ampicillin-resistant Enterococcus faecium using broth dilution minimum inhibitory concentrations (MICs) and time-kill studies. We tested 12 ampicillin-resistant isolates and demonstrated the following MICs and MBCs, respectively: ampicillin, greater than or equal to 32 micrograms/ml and greater than 256 micrograms/ml; daptomycin, less than or equal to 4 micrograms/ml and less than or equal to 16 micrograms/ml; and vancomycin, less than or equal to 4 micrograms/ml and greater than 64 micrograms/ml. Time-kill studies demonstrated that daptomycin alone had marked activity against the ampicillin-resistant E. faecium and that the addition of gentamicin resulted in synergistic killing. In addition, ampicillin and vancomycin were not bactericidal for the ampicillin-resistant isolates without the addition of gentamicin. The present study supports the consideration of daptomycin alone or in combination with an aminoglycoside as an alternative therapy for ampicillin-resistant enterococci, although additional clinical experience is now necessary.

Ampicillin↗
PubMedDate not supplied

Daptomycin cure after cefazolin treatment failure of Methicillin-sensitive Staphylococcus aureus (MSSA) tricuspid valve acute bacterial endocarditis from a peripherally inserted central catheter (PICC) line.

Right-sided acute bacterial endocarditis (ABE) is an infrequent complication of central intravenous (IV) lines. We report a case of methicillin-sensitive Staphylococcus aureus tricuspid valve (TV) ABE related to a peripherally inserted central catheter line (PICC). Patients with right-sided ABE present with symptoms of fever and chills, and symptoms and signs of pulmonary emboli. In the patient presented, the PICC line was removed and high-dose cefazolin therapy, 2 g (IV) every 8 hours, was initiated. Although the patient's blood cultures became negative during the third week of cefazolin therapy, her erythrocyte sedimentation rate and teichoic acid antibody titers remained high. Pulmonary emboli developed. A large TV vegetation (1 x 2 cm) remained unchanged after 4 weeks of cefazolin therapy. For these reasons, cefazolin treatment was considered a treatment failure. Therapy with daptomycin was initiated at a dose of 6 mg/kg (IV) every 24 hours. During daptomycin therapy, the patient's erythrocyte sedimentation rate and teichoic acid antibody titers gradually returned to normal. Repeat transthoracic echocardiograph revealed the TV vegetation was gone and the methicillin-sensitive Staphylococcus aureus ABE was cured with daptomycin. We conclude daptomycin is a rapidly bactericidal antistaphylococcal antibiotic reliably effective even when other usually effective antistaphylococcal antibiotics have failed.

Acute Disease↗
PubMed2004

Studies on the reactions between daptomycin and glyceraldehyde.

The objectives of this project were to determine the reaction pathways of daptomycin in the presence of glyceraldehyde in acidic solutions, and to quantitate the kinetics of the major pathways. In the presence of glyceraldehyde (pH range 1-7 at 25 to 60 degrees C), daptomycin formed two major products separable by RP-HPLC. The products were identified using UV spectroscopy, fluorimetry, mass spectrometry, and 2D-1H NMR. The reaction scheme involved the reversible formation of imine and anilide derivatives. Carbinolamine was believed to be a common intermediate in formation pathways of both products. The carbinolamine intermediate underwent either acid catalyzed dehydration resulting in imine formation or intramolecular hydrogen bonding and bond cleavage giving rise to anilide formation. In mild acid conditions, both products reversed to daptomycin. The reaction between daptomycin and glyceraldehyde was first-order with respect to both reactants. In a pH range of 1-7, the imine formation rate was pH dependent with a maximum rate at approximate pH values of 3-4. The observed pH dependence was consistent with the pH dependence of typical amine-aldehyde reactions.

Anilides↗
PubMed1993

Activity of daptomycin against enterococci and coagulase-negative staphylococci (CNS): relationship between CNS susceptibility and slime production.

We compared the in vitro activity of daptomycin, a new lipopeptide antibiotic, with that of vancomycin and other selected agents against 95 coagulase negative staphylococci (CNS) isolates causing septicemia or foreign-body infections in immunocompromised patients. These strains were classified as follows: 51 methicillin-susceptible CNS (23 slime producers); 44 methicillin-resistant CNS (23 slime producers). We also investigated the activity of daptomycin against 50 Enterococcus faecalis isolates. Minimal inhibitory concentrations (MICs) were determined by the broth microdilution method. Daptomycin at a concentration of 2 mg/L was inhibitory for all the evaluated strains. Vancomycin and ciprofloxacin showed good activity: 90% of the strains were inhibited by these agents at 8 mg/L. The activity of netilmicin, rifampin and trimethoprim-sulfamethoxazole was instead limited. Resistance to the antimicrobial agents tested was seen with increased frequency among slime producing strains. Daptomycin and teicoplanin were the most active agents tested against E. faecalis (MIC90 0.25 mg/L and 0.12 mg/L).

Anti-Bacterial Agents↗
PubMed2005

Inhibition of daptomycin by pulmonary surfactant: in vitro modeling and clinical impact.

The lipopeptide daptomycin has been approved for use in skin and skin-structure infections but has failed to meet statistical noninferiority criteria in a clinical trial for severe community-acquired pneumonia. Daptomycin exhibited an unusual pattern of activity in pulmonary animal models: efficacy in Staphylococcus aureus hematogenous pneumonia and inhalation anthrax but no activity against Streptococcus pneumoniae in simple bronchial-alveolar pneumonia. Daptomycin was shown to interact in vitro with pulmonary surfactant, resulting in inhibition of antibacterial activity. This effect was specific to daptomycin and consistent with its known mechanism of action. This represents the first example of organ-specific inhibition of an antibiotic.

Animals↗
PubMed1990

Influence of subinhibitory concentrations of loracarbef (LY 163892) and daptomycin (LY 146032) on bacterial phagocytosis, killing and serum sensitivity.

The aim of this study was to evaluate whether pre-exposure of bacteria to a subinhibitory concentration (sub-MIC) of loracarbef (LY 163892) or daptomycin (LY 146032) could modify bacterial susceptibility to serum bactericidal activity and to phagocytosis and killing by murine peritoneal macrophages and by human polymorphonuclear leucocytes. Escherichia coli, Haemophilus influenzae type b and Staphylococcus aureus grown in the presence of one quarter the MIC of loracarbef, and S. aureus exposed to one quarter the MIC of daptomycin were phagocytosed and killed in numbers significantly higher than non-exposed bacteria. Pre-exposure to loracarbef resulted in increased susceptibility of E. coli and H. influenzae type b to the bactericidal activity of antiserum, but exposure to loracarbef or daptomycin did not modify serum sensitivity of S. aureus. Loracarbef treatment and antiserum enhanced phagocytosis and killing of E. coli and H. influenzae type b to a greater extent than either antibiotic treatment or antiserum alone. These data indicate that loracarbef and daptomycin at sub-MIC enhance the susceptibility of bacterial pathogens to cellular and host defence mechanisms.

Bacteria↗
PubMed1993

The activity of daptomycin on Enterococcus faecium protoplasts: indirect evidence supporting a novel mode of action on lipoteichoic acid synthesis.

The effect of daptomycin, an acidic lipopeptide antibiotic active against Gram-positives, was studied in Enterococcus faecium protoplasts. This antibiotic killed 99% of the protoplasts within 60 minutes of treatment, while vancomycin was ineffective, thus excluding peptidoglycan synthesis as the only target of the action of daptomycin. As previously seen with whole cells, in protoplasts lipoteichoic acid synthesis was the earliest and most strongly inhibited among types of macro-molecular synthesis. Radioactive daptomycin tightly bound only to the cytoplasmic membrane, in which the enzymes involved in lipoteichoic acid synthesis are located. These conclusions strongly support our previous proposal that daptomycin, though active against peptidoglycan synthesis, primarily inhibits lipoteichoic acid synthesis.

Anti-Bacterial Agents↗
PubMed2003

Pharmacodynamic profile of daptomycin against Enterococcus species and methicillin-resistant Staphylococcus aureus in a murine thigh infection model.

OBJECTIVE: To describe the pharmacodynamic profile of daptomycin against methicillin-resistant Staphylococcus aureus (MRSA) and Enterococci species based on bacterial density in an immunocompromised mouse thigh infection model. MATERIALS AND METHODS: The pharmacodynamic (PD) profile of daptomycin was determined against two MRSA, one vancomycin-resistant Enterococcus faecium, and one vancomycin-susceptible Enterococcus faecalis using the immunocompromised murine thigh model. Efficacy was assessed by the change in log10 cfu in thighs after 24 h of drug treatment. RESULTS: Daptomycin produced a maximal kill of 4.5-5 log10 cfu against the MRSA and 1.5-2 log10 for the Enterococcus species. AUC/MIC was the most predictive of the PD parameters. Utilizing MICs determined in serum or broth in the calculation of the PD parameters had minimal effect on this correlation. AUCfree/MICbroth required for static effects with MRSA and Enterococcus species were 12-36 and 5-13, whereas 99% of maximal kill was achieved at ratios of 171-442 and 38-157, respectively. CONCLUSIONS: These data reveal the potent in vivo bactericidal activity of daptomycin against MRSA and Enterococcus species using clinically achievable drug exposures (dose 4-6 mg/kg per day) currently under investigation in man.

Animals↗
PubMed2006

Uncertain efficacy of daptomycin for prosthetic joint infections: a prospective case series.

Daptomycin is an option for prosthetic joint infection (PJI) because it is bactericidal against gram-positive bacteria, including multiple-resistant isolates, and active against stationary-phase bacteria in biofilm present on implants. To evaluate its possible utility, we prospectively monitored 12 adults with gram-positive PJI who were not candidates for vancomycin. Pathogens included methicillin-resistant Staphylococcus aureus (n = 7), methicillin-resistant-coagulase-negative Staphylococci (n = 4), and methicillin-sensitive Staphylococcus aureus (n = 1). All patients completed a 6-week course of daptomycin 4 mg/kg/day. One died of an unrelated cause shortly after completing therapy. After a followup of 7 to 13 months, six patients had no clinical, laboratory, or radio-graphic signs of recurrence. One patient failed a first course and was subsequently treated with hardware removal and a second course with no recurrence. Five patients had culture-confirmed failure-all due to MRSA-including two during therapy despite hardware removal and three 1 to 10 months after completing daptomycin but with retained hardware. The efficacy of daptomycin 4 mg/kg/day is uncertain in patients with PJI, especially when hardware is retained. Further study is needed to determine why in vitro data did not predict clinical success and to ascertain any potential benefit from higher doses.

Aged↗