Friday, November 17, 2006

What is a prodrug?

The Wikipedia entry on colistin notes that colistimethate is an "inactive prodrug of colistin" - this portion of the entry seems to be directly related to this laboratory study by Bergen et al. published in the June 2006 issue of Antimicrobial Agents and Chemotherapy, which reports to be the first study establishing that colistimethate is a prodrug, though this article is not cited in the Wikipedia entry. defines "prodrug" as an "inactive precursor of a drug, converted into its active form in the body by normal metabolic processes" (there's also a brief Wikipedia entry on prodrugs) -- the classification of colistimethate as a prodrug by Bergen et al. implies that colistimethate on its own is inactive, but is converted (i.e. metabolized) to colistin after injected into the human body.

This may have significant implications for susceptibility testing - exposing cultured bacteria to colistimethate may provide incorrect estimates of the antibiotic's activity against the bacteria, as conversion within the body to the active form via hydrolysis may be required (Bergen et al. recommend that colistin should be used for these kinds of assays).

As you review the studies published in the literature, this consideration may help you with assessing and critiquing the microbiological assays employed in the studies, as well as any pharmacokinetic and pharmacodynamic investigations. This information would also be key if the initial question about colistin prompted additional follow-up questions such as "How well do microbiological assays perform with respect to colistin sensitivity?" or "How do we determine if we're administering 'enough' colistin to the patient?"

Related link:
The article by Bergen et al. mentions the "Bad Bugs, No Drugs" campaign launched by the Infectious Diseases Society of America, subtitled "As Antibiotic Discovery Stagnates . . . A Public Health Crisis Brews." The campaign includes a white paper, press materials, description of sponsored legislation, and key statistics on the growing problem of antimicrobial resistance among some bacterial strains.


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