In Vivo Pharmacodynamics of a New Oxazolidinone (Linezolid)

Abstract

The number of infections due to resistant gram-positive bacteria, including penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus, and vancomycinresistant Enterococcus faecium, continues to increase (8,10,12,17). The development of effective antimicrobial agents to treat these infections is an area of intense research. Oxazolidinone antimicrobial agents represent a promising new class of compounds which act by inhibiting protein synthesis and have demonstrated potency against these emerging pathogens (13, 16; R. N. Jones, M. A. Pfaller, M. E. Erwin, and M. L. Beach, Abstr. 37th Infect. Dis. Soc. Am. Annu. Meet., abstr. 97, 1999).Linezolid is a new oxazolidinone that has demonstrated both in vitro activity and in vivo efficacy in animal models and clinical trials (2, 13, 15; Jones et al., Abstr. 37th Infect. Dis. Soc. Am. Annu. Meet.). The goals of our studies were (i) to characterize the in vivo time course of antimicrobial activity of linezolid against susceptible and resistant S. pneumoniae and S. aureus strains and (ii) to determine the PK/PD parameter and the magnitude of the PK/PD parameter predictive of efficacy.(Part of this work was presented at the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, Calif., September 1998.) MATERIALS AND METHODSBacteria, media, and antibiotic. Eight strains of S. pneumoniae (one penicillinsusceptible, two penicillin-intermediate, and five penicillin-resistant S. pneumoniae strains) and four strains of S. aureus (two methicillin-susceptible and two methicillin-resistant S. aureus strains) were used for these experiments. S. aureus and S. pneumoniae organisms were grown, subcultured, and quantified in Mueller-Hinton broth (Difco Laboratories, Detroit, Mich.), on Mueller-Hinton agar (Difco Laboratories, Detroit, Mich.), and on sheep blood agar plates (Remel, Milwaukee, Wis.). Linezolid was supplied by Pharmacia & Upjohn Company, Kalamazoo, Mich.In vitro susceptibility studies. The MICs of linezolid, penicillin, and methicillin for the various isolates were determined by using standard National Committee for Clinical Laboratory Standards microdilution methods.Murine infection model. Six-week-old, specific-pathogen-free, female ICR/ Swiss mice weighing 23 to 27 g (Harlan Sprague-Dawley, Madison, Wis.) were used for all studies. All animal studies were approved by the Animal Research Committee of the William S. Middleton Memorial VA Hospital. Mice were rendered neutropenic (neutrophils at Ͻ100/mm 3 ) by injecting cyclophosphamide (Mead Johnson Pharmaceuticals, Evansville, Ind.) intraperitoneally 4 days (150 mg/kg) and 1 day (100 mg/kg) before experimental infection. Previous studies have shown that this regimen produces neutropenia in this model for 5 days (1). Broth cultures of freshly plated bacteria were grown to logarithmic phase overnight to an absorbance of 0.3 at 580 nm (Spectronic 88; Bausch and Lomb, Rochester, N.Y.). After a 1:10 dilution into fresh Mueller-Hinton broth, bacterial counts of the ...

Translational Pharmacometric Evaluation of Typical Antibiotic Broad-Spectrum Combination Therapies AgainstStaphylococcus AureusExploitingIn VitroInformation

“…Last, we also assessed the relation of the semimechanistic PK‐PD model to typically utilized PK‐PD indices and breakpoints that are used in a clinical setting. For LZD, the determined value of 56 for f AUC/MIC in the present work is fairly close to the breakpoints in animals (AUC/MIC of 83)37 and humans (AUC/MIC of 51–85)38 for bloodstream infections if protein binding is considered. For MER, the determined value of 52% f %T >MIC was also in good agreement with the clinical breakpoint for microbiological response of 54% determined in patients with lower respiratory tract infections, in which S. aureus was the second‐most abundant pathogen 39.…”

In Vivo Pharmacokinetics and Pharmacodynamics of ZTI-01 (Fosfomycin for Injection) in the Neutropenic Murine Thigh Infection Model against Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa

“…This is consistent with AUC/MIC ratio as the pharmacodynamically linked index and supports our findings. The importance of the AUC/MIC ratio index for this compound with concentration-independent killing is reminiscent of PK/PD characteristics of the oxazolidinones and triazoles (24)(25)(26). One reason for this observed outcome in our dose fractionation study could be due to postantibiotic effects (PAEs).…”

Comparative Pharmacodynamics of the New Oxazolidinone Tedizolid Phosphate and Linezolid in a Neutropenic Murine Staphylococcus aureus Pneumonia Model

“…While the index associated with therapeutic success has been extensively examined, few studies have attempted to identify the AUC/MIC magnitude or target associated with efficacy in treatment against MSSA or MRSA. In an in vivo study of linezolid using a neutropenic murine thigh infection model, the PD index AUC/ MIC provided the best correlation with efficacy and the static dose target was a fAUC/MIC of 58 (8). A single clinical PK/PD study examined linezolid efficacy in patients with MRSA cellulitis, bacteremia, and pneumonia (44).…”

“…The dose needed to achieve net stasis (SD) and 1-log-unit kill was determined using the formula for each drug against each strain tested. The area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) has been shown in previous studies to be the pharmacodynamic (PD) parameter predictive of treatment efficacy for oxazolidinones (8,35). Therefore, the total drug AUC/MIC (tAUC/MIC ratio) and free drug (non-protein-bound) AUC/MIC (fAUC/MIC ratio) for each drug-organism combination was also determined.…”