ly-146032 and Neutropenia

Daptomycin is the first antibacterial agent of the cyclic lipopeptides with in vitro bactericidal activity against gram-positive organisms, including vancomycin-resistant enterococci, methicillin-resistant staphylococci, and glycopeptide-resistant Staphylococcus aureus. The pharmacokinetics of daptomycin were determined in 29 adult oncology patients with neutropenic fever. Serial blood samples were drawn at 0, 0.5, 1, 2, 4, 8, 12, and 24 h after the initial intravenous infusion of 6 mg/kg of body weight daptomycin. Daptomycin total and free plasma concentrations were determined by high-pressure liquid chromatography. Concentration-time data were analyzed by noncompartmental methods. The results (presented as means +/- standard deviations and ranges, unless indicated otherwise) were as follows: the maximum concentration of drug in plasma (C(max)) was 49.04 +/- 12.42 microg/ml (range, 21.54 to 75.20 microg/ml), the 24-h plasma concentration was 6.48 +/- 5.31 microg/ml (range, 1.48 to 29.26 microg/ml), the area under the concentration-time curve (AUC) from time zero to infinity was 521.37 +/- 523.53 microg.h/ml (range, 164.64 to 3155.11 microg.h/ml), the volume of distribution at steady state was 0.18 +/- 0.05 liters/kg (range, 0.13 to 0.36 liters/kg), the clearance was 15.04 +/- 6.09 ml/h/kg (range, 1.90 to 34.76 ml/h/kg), the half-life was 11.34 +/- 14.15 h (range, 5.17 to 83.92 h), the mean residence time was 15.67 +/- 20.66 h (range, 7.00 to 121.73 h), and the median time to C(max) was 0.6 h (range, 0.5 to 2.5 h). The fraction unbound in the plasma was 0.06 +/- 0.02. All patients achieved C(max)/MIC and AUC from time zero to 24 h (AUC(0-24))/MIC ratios for a bacteriostatic effect against Streptococcus pneumoniae. Twenty-seven patients (93%) achieved a C(max)/MIC ratio for a bacteriostatic effect against S. aureus, and 28 patients (97%) achieved an AUC(0-24)/MIC ratio for a bacteriostatic effect against S. aureus. Free plasma daptomycin concentrations were above the MIC for 50 to 100% of the dosing interval in 100% of patients for S. pneumoniae and 90% of patients for S. aureus. The median time to defervescence was 3 days from the start of daptomycin therapy. In summary, a 6-mg/kg intravenous infusion of daptomycin every 24 h was effective and well tolerated in neutropenic cancer patients.

Topics: Adult; Aged; Animals; Anti-Bacterial Agents; Antineoplastic Agents; Area Under Curve; Biological Assay; Daptomycin; Ethnicity; Female; Fever; Half-Life; Humans; Injections, Intravenous; Male; Mice; Middle Aged; Neoplasms; Neutropenia; Obesity, Morbid; Sex Characteristics; Staphylococcus aureus; Streptococcus pneumoniae; Young Adult

The rising rates of antibiotic resistance accentuate the critical need for new antibiotics. Daptomycin is a new antibiotic with a unique mode of action and a rapid in vitro bactericidal effect against gram-positive organisms. This study examined the kinetics of daptomycin's bactericidal action against peritonitis caused by methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) in healthy and neutropenic mice and compared this activity with those of other commonly used antibiotics. CD-1 mice were inoculated intraperitoneally with lethal doses of MSSA (Xen-29) or MRSA (Xen-1), laboratory strains transformed with a plasmid containing the lux operon, which confers bioluminescence. One hour later, the animals were given a single dose of daptomycin at 50 mg/kg of body weight subcutaneously (s.c.), nafcillin at 100 mg/kg s.c., vancomycin at 100 mg/kg s.c., linezolid at 100 mg/kg via gavage (orally), or saline (10 ml/kg s.c.). The mice were anesthetized hourly, and photon emissions from living bioluminescent bacteria were imaged and quantified. The luminescence in saline-treated control mice either increased (neutropenic mice) or remained relatively unchanged (healthy mice). In contrast, by 2 to 3 h postdosing, daptomycin effected a 90% reduction of luminescence of MSSA or MRSA in both healthy and neutropenic mice. The activity of daptomycin against both MSSA and MRSA strains was superior to those of nafcillin, vancomycin, and linezolid. Against MSSA peritonitis, daptomycin showed greater and more rapid bactericidal activity than nafcillin or linezolid. Against MRSA peritonitis, daptomycin showed greater and more rapid bactericidal activity than vancomycin or linezolid. The rapid decrease in the luminescent signal in the daptomycin-treated neutropenic mice underscores the potency of this antibiotic against S. aureus in the immune-suppressed host.

Topics: Acetamides; Animals; Anti-Bacterial Agents; Colony Count, Microbial; Daptomycin; Female; Linezolid; Luminescent Measurements; Methicillin Resistance; Mice; Microbial Sensitivity Tests; Neutropenia; Oxazolidinones; Peritonitis; Staphylococcus aureus