Postantibiotic Effects of Daptomycin against 14 Staphylococcal and Pneumococcal Clinical Isolates

Abstract

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...

Antimicrobial Properties of MX-2401, an Expanded-Spectrum Lipopeptide Active in the Presence of Lung Surfactant

“…Other observed microbiological properties of MX-2401 include the low frequency of spontaneous resistance, the low potential for emergence of resistance, and a long in vitro PAE, consistent with bacterial cell damage during exposure that impacts the growth fitness of bacteria. The PAE of MX-2401 was similar to or slightly longer than those of vancomycin and daptomycin as reported in our study and in keeping with literature values for the latter two antibiotics (7,21). The long PAE was also observed in in vivo studies (9).…”

Daptomycin: A Review 4 Years after First Approval

“…The effect of subinhibitory drug levels following suprainhibitory levels which persist between dosing intervals is referred to as the postantibiotic sub-MIC effect (PA-SME). Staphylococcal PA-SME effects at 0.4 times the MIC ranged from 3.0 h to 1 12 h [17] . PA-SMEs and PAEs for S. aureus and Enterococcus faecalis were dosedependent, and it was concluded that the relatively high PA-SME and PAE values found in vitro support oncedaily dosing of daptomycin [17,18] .…”

“…Daptomycin staphylococcal PAE ranged from approximately 1.1 to 6.2 h, with a mean of 2.5 h [17,18] . The effect of subinhibitory drug levels following suprainhibitory levels which persist between dosing intervals is referred to as the postantibiotic sub-MIC effect (PA-SME).…”

Daptomycin: Pharmacokinetic, Pharmacodynamic, and Dose Optimization

“…Daptomycin MIC 90 values are typically 0.25-0.5, 1, and 0.25 mg/L for Staphylococci spp., vancomycin-susceptible Enterococci spp., and group B Streptococci spp., respectively (Sader et al 2005 ). Daptomycin also exhibits a prolonged and dose-dependent PAEs (from 1.1 to 6.2 h against S. aureus and in the 1 to 2.5 h range against S. pneumoniae ) (Hanberger et al 1991 ;Safdar et al 2004 ;Pankuch et al 2003 ). Unfortunately, the ability of these PD parameters to predict clinical effi cacy is limited since they do not take into account any interactions of the drug or its penetration at the site of infection.…”