Linezolid, Levofloxacin, and Vancomycin Against Vancomycin-Tolerant and Fluoroquinolone-Resistant Streptococcus pneumoniae in an In Vitro Pharmacodynamic Model

Raymond Cha, Pharm.D.; Ronda L. Akins, Pharm.D.; Michael J. Rybak, Pharm.D., M.S., FCCP


Pharmacotherapy. 2003;23(12) 

In This Article

Abstract and Introduction

Study Objective: To compare the pharmacodynamic profiles of linezolid, levofloxacin, and vancomycin against clinical strains of Streptococcus pneumoniae, including vancomycin-tolerant and fluoroquinolone-resistant isolates.
Design: In vitro pharmacodynamic model.
Setting: Biosafety level 2, university research laboratory.
Bacterial Strains: Ciprofloxacin-susceptible (79), ciprofloxacin-resistant (R921), and vancomycin-tolerant (P9802-020) clinical strains of S. pneumoniae.
Intervention: An in vitro pharmacodynamic model was used to simulate standard dosing regimens of linezolid, levofloxacin, and vancomycin against the isolates 79, R921, and P9802-020.
Measurements and Main Results: Bacterial density was profiled over 48 hours. Minimum inhibitory concentrations (MICs) for linezolid, levofloxacin, and vancomycin, respectively, were 1, 1, 0.5 µg/ml for isolate 79; 1, 4, 0.5 µg/ml for R921; and 0.5, 0.5, 0.5 µg/ml for P9802-020. Vancomycin minimum bactericidal concentration (MBC) values varied across large ranges for the tested strains. Linezolid achieved 99.9% kill against 79 and R921 by 24 and 28 hours, respectively. Levofloxacin achieved 99.9% kill against 79 and P9802-020 by 28 and 4 hours, respectively. Vancomycin achieved 99.9% kill against 79 and R921 by 8 and 24 hours, respectively. Levofloxacin did not demonstrate activity against R921 at the 48-hour end point. Minimal kill (< 2 log) at 48 hours was noted for vancomycin and linezolid against P9802-020.
Conclusion: Vancomycin tolerance appeared to be more reliably characterized by persistent viability in time-kill analyses than by MBC:MIC ratios. Vancomycin exhibited bactericidal activity against the non-vancomycin-tolerant strains of S. pneumoniae. Linezolid exhibited both bactericidal and bacteriostatic activity against all three strains tested, whereas levofloxacin demonstrated bactericidal activity against the fluoroquinolone-susceptible isolates. Further investigation of treatment alternatives for infections due to vancomycin-tolerant S. pneumoniae are needed.

Antimicrobial resistance among gram-positive bacteria has become increasingly prevalent and has been paralleled by the occurrence of serious bacteremia, pneumonia, meningitis, and otitis media caused by Streptococcus pneumoniae.[1,2,3,4] The burden of drug-resistant S. pneumoniae has increased by more than 8% to an overall prevalence of about 30% in the United States and Canada.[1,5] Furthermore, pneumococci with reduced susceptibility to fluoroquinolones have been described in Canada, Hong Kong, Spain, and the United States.[3,6,7,8,9] This is a serious challenge due to diminution of potential treatment options and requires a multidisciplinary approach in conjunction with improved clinical strategies to limit further occurrences of multidrug-resistant S. pneumoniae infections.

Adding to this problem is the first report, to our knowledge, of a S. pneumoniae isolate that exhibited tolerance to vancomycin based on in vitro viability analyses.[10] That report soon was followed by the first characterization of a recrudescent meningitis infection due to S. pneumoniae that showed tolerance to vancomycin based on clinical presentation and was confirmed by in vitro time-kill analyses.[11] The potential for further identification of infections due to vancomycin-tolerant S. pneumoniae substantiates the need for evaluation of treatment options. To date, published data on assessment of antimicrobials against this pathogen are limited to vancomycin in time-kill analyses and observational data from one clinical report.[10,11]

Potential alternatives consist of two classes of antimicrobials that exhibit non-cell-wall-mediated mechanisms of action: oxazolidinones and fluoroquinolones. Linezolid, a new synthetic agent belonging to the oxazolidinone class of antibiotic, has broad antimicrobial activity against a variety of gram-positive bacteria, including resistant organisms. The agent acts like no other at the 50S ribosomal target site responsible for initiation of protein synthesis and has demonstrated no cross-resistance to other antimicrobials thus far.[12,13] The spectrum of activity, mechanism of activity, and favorable pharmacokinetics of linezolid establish it as a potential agent in the treatment of resistant gram-positive infections. Extended-spectrum fluoroquinolones possess enhanced gram-positive coverage and have increased dramatically in use as a result of their distinctively characteristic mechanism of activity (inhibition of DNA gyrase and/or topoisomerase IV), antimicrobial spectrum, and favorable pharmacokinetic profiles.[14,15] We chose to characterize the activity of linezolid and levofloxacin compared with that of vancomycin against vancomycin-tolerant and -sensitive clinical strains of S. pneumoniae in an in vitro pharmacodynamic model.


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