Pharmacokinetics and tolerability of lefamulin following intravenous and oral dosing.

OBJECTIVES: To explore the pharmacokinetics (PK) of oral and intravenous (iv) lefamulin after single and multiple doses, and the effect of food on bioavailability. METHODS: Lefamulin PK was examined in four studies. In Study 1, PK was assessed in patients with acute bacterial skin and skin structure infections who received repeated iv lefamulin q12h (150 mg). In Study 2, a four-period crossover study, healthy subjects received a single dose of oral lefamulin [immediate-release (IR) tablet, 1 × 600 mg] in a fasted and fed state, oral lefamulin (capsule, 3 × 200 mg) in a fasted state, and iv lefamulin in a fasted state. In Study 3, a three-period crossover study, healthy males received a single oral lefamulin dose (IR) in the following states: fasted, fasted followed by a high-calorie meal 1 h post-dose, and fed. Study 4 had two parts; in part A, healthy males received a single lefamulin dose (IR) in a fasted and fed state; in part B, subjects received repeated doses of lefamulin (IR, q12h) or placebo. Adverse events (AEs) were recorded in each study. RESULTS: Single and repeated dosing of iv and oral lefamulin resulted in comparable exposure. Intravenous and oral lefamulin (given fasted or with a meal 1 h post-dose) resulted in bioequivalence. Bioequivalence was not established between oral lefamulin in the fed state and iv or oral administration in the fasted state. All AEs were mild or moderate in severity, no serious AEs were reported, and no participant discontinued because of an AE. CONCLUSIONS: The PK of lefamulin supports successful switch from iv to oral therapy; lefamulin was generally well tolerated.

Mechanistic basis for the action of new cephalosporin antibiotics effective against methicillin- and vancomycin-resistant Staphylococcus aureus.

Emergence of methicillin-resistant Staphylococcus aureus (MRSA) has created challenges in treatment of nosocomial infections. The recent clinical emergence of vancomycin-resistant MRSA is a new disconcerting chapter in the evolution of these strains. S. aureus normally produces four PBPs, which are susceptible to modification by beta-lactam antibiotics, an event that leads to bacterial death. The gene product of mecA from MRSA is a penicillin-binding protein (PBP) designated PBP 2a. PBP 2a is refractory to the action of all commercially available beta-lactam antibiotics. Furthermore, PBP 2a is capable of taking over the functions of the other PBPs of S. aureus in the face of the challenge by beta-lactam antibiotics. Three cephalosporins (compounds 1-3) have been studied herein, which show antibacterial activities against MRSA, including the clinically important vancomycin-resistant strains. These cephalosporins exhibit substantially smaller dissociation constants for the preacylation complex compared with the case of typical cephalosporins, but their pseudo-second-order rate constants for encounter with PBP 2a (k(2)/K(s)) are not very large (< or =200 m(-1) s(-1)). It is documented herein that these cephalosporins facilitate a conformational change in PBP 2a, a process that is enhanced in the presence of a synthetic surrogate for cell wall, resulting in increases in the k(2)/K(s) parameter and in more facile enzyme inhibition. These findings argue that the novel cephalosporins are able to co-opt interactions between PBP 2a and the cell wall in gaining access to the active site in the inhibition process, a set of events that leads to effective inhibition of PBP 2a and the attendant killing of the MRSA strains.