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

147

102

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 (V 2 ) and intercompartmental clearance (Q) were linearly related to body weight. V 2 increased approximately twofold in the presence of an acute infection. No factors were identified that significantly impacted V 1 . 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. Daptomycin

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics of Daptomycin

Dvorchik

Arbeit

Chung³

et al. 2004

147

102

“…Daptomycin is a lipopeptide antibiotic derived from Streptomyces roseosporus. Among its attributes, daptomycin has potent bactericidal activity against a wide range of gram-positive bacteria (6, 7, 11-14, 16, 18, 21), including methicillin-resistant Staphylococcus aureus (8,9), VRE (1), and penicillin-resistant Streptococcus pneumoniae (5,20). Daptomycin is bactericidal against enterococci, including VRE, at concentrations near the MIC (1).…”

mentioning

confidence: 99%

In Vivo Pharmacodynamic Activity of Daptomycin

Safdar

Andes

Craig

2004

336

215

Daptomycin is a lipopeptide antibiotic with activity against a wide range of gram-positive bacteria. We used the neutropenic murine thigh model to characterize the pharmacodynamics of daptomycin. ICR/Swiss mice were rendered neutropenic with cyclophosphamide; and the thigh muscles of the mice were infected with strains of Staphylococcus aureus, Streptococcus pneumoniae, and Enterococcus faecium. Animals were treated by subcutaneous injection of daptomycin at doses of 0.20 to 400 mg/kg of body weight/day divided into one, two, four, or eight doses over 24 h. Daptomycin exhibited linear pharmacokinetics, with an area under the concentration-time curve (AUC) from time zero to infinity/dose of 9.4 and a half-life of 0.9 to 1.4 h. The level of protein binding was 90%. Free daptomycin exhibited concentration-dependent killing and produced in vivo postantibiotic effects (PAEs) of 4.8 to 10.8 h. Nonlinear regression analysis was used to determine which pharmacokinetic (PK) or pharmacodynamic (PD) parameter was important for efficacy by using free drug concentrations. The peak concentration/MIC (peak/MIC) ratio and 24-h AUC/MIC ratio were the PK and PD parameters that best correlated with in vivo efficacy (R 2 ‫؍‬ 83 to 87% for peak/MIC and R 2 ‫؍‬ 86% for the AUC/MIC ratio, whereas R 2 ‫؍‬ 47 to 50% for the time that the concentration was greater than the MIC) against standard strains of S. aureus and S. pneumoniae. The peak/MIC ratios required for a bacteriostatic effect ranged from 12 to 36 for S. pneumoniae, 59 to 94 for S. aureus, and 0.14 to 0.25 for E. faecium. The AUC/MIC ratios needed for a bacteriostatic effect ranged from 75 to 237 for S. pneumoniae, 388 to 537 for S. aureus, and 0.94 to 1.67 for E. faecium. The free daptomycin concentrations needed to average from one to two times the MIC over 24 h to produce a bacteriostatic effect and two to four times the MIC over 24 h to produce greater than 99% killing. The long PAE and potent bactericidal activity make daptomycin an attractive option for the treatment of infections caused by gram-positive bacteria.

“…The effect of sub-MICs on growth during the PAE period has been defined as the postantibiotic sub-MIC effect (PA-SME), representing the time interval that includes the PAE plus the additional time during which growth is suppressed by subMICs. In contrast to the PA-SME, the SME measures the direct effect of subinhibitory levels on cultures which have not been previously exposed to antibiotics (13-15).We examined the PAE, PA-SME, and SME of daptomycin, a lipopeptide active against gram-positive organisms (1,2,6,8,(16)(17)(18). We studied two clinical strains each of methicillinsusceptible Staphylococcus aureus, methicillin-resistant S. aureus, methicillin-susceptible coagulase-negative staphylococci, methicillin-resistant coagulase-negative staphylococci, and penicillin-susceptible, -intermediate, and -resistant Streptococcus pneumoniae.…”

mentioning

confidence: 99%

“…We examined the PAE, PA-SME, and SME of daptomycin, a lipopeptide active against gram-positive organisms (1,2,6,8,(16)(17)(18). We studied two clinical strains each of methicillinsusceptible Staphylococcus aureus, methicillin-resistant S. aureus, methicillin-susceptible coagulase-negative staphylococci, methicillin-resistant coagulase-negative staphylococci, and penicillin-susceptible, -intermediate, and -resistant Streptococcus pneumoniae.…”

mentioning

confidence: 99%

Postantibiotic Effects of Daptomycin against 14 Staphylococcal and Pneumococcal Clinical Isolates

Pankuch

Jacobs

Appelbaum

2003

Daptomycin mean staphylococcal postantibiotic effects (PAEs) were 1.1 to 6.2 h, with a mean of 2.5 h. The mean pneumococcal PAEs were 1.7 h, ranging between 1.0 and 2.5 h. The staphylococcal and pneumococcal postantibiotic sub-MIC effects at 0.4 times the MIC ranged from 3.0 to >12.0 h and 1.9 to >12.0 h, respectively.The postantibiotic effect (PAE) is a pharmacodynamic parameter contributing to the choosing of antibiotic dosing regimens. It is defined as the length of time that bacterial growth is suppressed following brief exposure to an antibiotic (4, 5, 10). Odenholt-Tornqvist and coworkers have suggested that during intermittent dosage regimens, suprainhibitory levels of antibiotic are followed by subinhibitory levels that persist between doses, and those authors have hypothesized that persistent subinhibitory levels could extend the PAE (3, 13-15). The effect of sub-MICs on growth during the PAE period has been defined as the postantibiotic sub-MIC effect (PA-SME), representing the time interval that includes the PAE plus the additional time during which growth is suppressed by subMICs. In contrast to the PA-SME, the SME measures the direct effect of subinhibitory levels on cultures which have not been previously exposed to antibiotics (13-15).We examined the PAE, PA-SME, and SME of daptomycin, a lipopeptide active against gram-positive organisms (1,2,6,8,(16)(17)(18). We studied two clinical strains each of methicillinsusceptible Staphylococcus aureus, methicillin-resistant S. aureus, methicillin-susceptible coagulase-negative staphylococci, methicillin-resistant coagulase-negative staphylococci, and penicillin-susceptible, -intermediate, and -resistant Streptococcus pneumoniae. Organisms were identified by standard methods (11). No attempt was made to identify coagulase-negative staphylococci by species. Daptomycin MICs were determined by macrodilution procedures (12). Mueller-Hinton broth was adjusted to contain 50 mg of calcium per liter for testing daptomycin, as recommended by the NCCLS (12).The PAE was determined by the viable plate count method (5), using Mueller-Hinton broth supplemented with calcium as described above and 5% lysed horse blood when testing pneumococci. The PAE was induced by exposure to 10 times the MIC of daptomycin for 1 h. Because the protein binding of daptomycin is 90 to 92%, this corresponds to total serum drug concentrations of approximately 100 times the MIC and approximates serum free drug levels at peak concentrations only (8, 18).For PAE testing, tubes containing 5 ml of broth with antibiotic were inoculated with approximately 5 ϫ 10 6 CFU/ml. Inocula were prepared by suspending growth from an overnight blood agar plate in broth. Growth controls with inoculum but no antibiotic were included with each experiment. Inoculated test tubes were placed in a shaking water bath at 35°C for an exposure period of 1 h. At the end of the exposure period, cultures were diluted 1:1,000 in prewarmed broth to remove the antibiotic by dilution. Antibiotic removal was confirmed by compari...