Influence of Human Serum on Pharmacodynamic Properties of an Investigational Glycopeptide, LY333328, and Comparator Agents against Staphylococcus aureus

Abstract

The MICs and MBCs of 15 antibiotics for two strains ofStaphylococcus aureus were determined in Mueller-Hinton broth (MHB) and 90% serum–10% MHB. Subsequent experiments established that highly protein-bound antibiotics (≥80%), such as LY333328, demonstrated higher MICs and MBCs, less killing over an 8-h interval, and shorter postantibiotic effects in 90% serum–10% MHB than in MHB alone. Albumin was demonstrated to be almost solely responsible for changes in the aforementioned pharmacodynamic parameters of LY333328.

Emerging Treatment Options for Complicated Skin and Skin Structure Infections: Oritavancin

“…Because oritavancin is highly protein-bound (>80%), albumin is another factor that must be considered. 35 When tested in bovine serum albumin, oritavancin showed reduced activity (99.9% verses 5% killing of S. aureus with oritavancin for control and bovine serum albumin media, respectively) as well as a shorter post-antibiotic effect (65 minutes vs 5 minutes, respectively). 35 Further study is warranted to determine if this finding is clinically relevant.…”

Sensitivity of Antibacterial Activity to Backbone Sequence in Constitutionally Isomeric OligoTEAs

“…Selectivity for bacteria over mammalian cells is attributed to the reduced anionic character of the mammalian cell membrane and its rigidity due to the presence of cholesterol . While some AMPs display potent cell lysis, they generally suffer from reduced activity in serum containing physiological fluids due to protease degradation and protein binding . To combat these drawbacks, recent efforts have been made toward synthesizing AMP mimics comprised of proteolytic‐resistant backbones.…”

Oritavancin: An investigational lipoglycopeptide antibiotic

“…44 In general, the activity of oritavancin was not influenced by the growth phase of the evaluated organisms or the pH of the environment when the compound was tested against susceptible organisms; however, when tested against vancomycin-resistant E. faecium, it was found to have reduced activity against stationary-growth-phase isolates and in an acidic environment, both of which conditions are typical of endocarditis and abscesses. 45 The activity of oritavancin is affected by the inoculum size and by plasma proteins, as evidenced by higher MICs and MBCs, less killing activity, and shorter postantibiotic effect in serum versus MuellerHinton broth, 46 but the effect can be compensated for by increasing the dose. 47 Oritavancin displays in vitro concentration-dependent durations of postantibiotic effect of 2.4-7.7 hours for MRSA; for vancomycinresistant E. faecium, durations of postantibiotic effect have been variously reported as 1.9-4.3 and 18.7 hours.…”