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The oxazolidinones

Abstract number: 1133_189

Moellering R.

The oxazolidinones represent the only unique class of antimicrobials developed in the past 20 years. Originally synthesized as monoamine oxidase inhibitors, molecular manipulation has resulted in compounds with acceptable toxic : therapeutic ratios and outstanding activity against resistant gram-positive pathogens. Linezolid is the first of these compounds to be successfully developed for clinical use. The oxazolidinones have a unique mechanism of action, inhibiting the formation of the initiation complex in ribosomal protein synthesis. Resistance develops via mutations in the 23S rRNA gene. Since most of the important gram-positive pathogens have multiple copies of this gene and it requires more than a single mutation to develop clinical resistance, bacteria have been slow to develop immunity to these compounds. The oxazolidinones also exhibit excellent bioavailability and outstanding tissue penetration. They show little or no interaction with the cytochrome P450 system and they have been shown to be clinically effective. Nonetheless, the currently available oxazolidinone, linezolid, does have certain disadvantages. The MICs are near the breakpoints for many susceptible organisms (and above for H. influenzae and M. pneumoniae). The drug is bacteriostatic or only slowly bactericidal and failures in endocarditis have been reported. Although toxicity has not been an issue in standard courses of therapy, myelosuppression, peripheral neuropathy, and optic neuritis have been seen in patients receiving the drug for long periods of time. This has proven to be a disadvantage in its application for infections such as Nocardia and tuberculosis (both organisms of which are susceptible to linezolid) because of the long duration of therapy involved. It has outstanding penetration in the CSF, but formal studies evaluating it in meningitis have not been performed. Because of its relatively short half-life, it must be given twice a day. A number of new oxazolidinones are being developed in an attempt to improve on the valuable properties of linezolid. Although none of these has yet reached the clinic, they will receive further discussion.

Session Details

Date: 01/08/2007
Time: 00:00-00:00
Session name: XXIst ISTH Congress
Subject:
Location: Oxford, UK
Presentation type:
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