No New Antibiotics? Go to the Attic, Build Better Mousetraps

Paul G. Auwaerter, MD


June 27, 2017

Hi. Paul Auwaerter with Medscape Infectious Diseases. I'm speaking from the Johns Hopkins Division of Infectious Diseases. Many of us in ID wring our hands and voice a lot of consternation at the rather slow pace of the development of new antibiotic agents, especially as resistance issues really seem to increase month by month and year by year. With necessity being the mother of invention, an old Plato attribution, both scientists and clinicians have either gone to the attic or tried to help improve old drugs to see if we can get a bit more mileage with agents that we already have.

There are a couple of stories that I thought might be interesting here that have been recently published or discussed. The first is ethionamide,[1] a drug for tuberculosis that really has been relegated to lower-tier status, mainly because of rather profound gastrointestinal side effects, orthostasis, and even CNS toxicity. This is unusual in that it's a prodrug that actually has to be metabolized by an enzyme produced by Mycobacterium tuberculosis. Because of that, resistance is also an issue.

Scientists have found a compound that actually helps reverse resistance, at least in an infectious mouse model, with organisms inherently resistant to the drug alone. This agent SMARt-420[2] seems to help amplify production of active drug (metabolism of the prodrug) by increasing the amount of enzymatic activities. This is a rather novel way of using an old drug that might be much more effective without causing any greater toxicity (hopefully lower toxicities), so stay tuned there.

Vancomycin, for many and for me especially, is probably the drug that I use the most that I hate the most, because of dosing difficulties, need for monitoring, and so on. Boger and colleagues[3] have tinkered with the drug using three different substitutions for the basic molecule that have overcome resistance issues with vancomycin-resistant enterococci (VRE). It can still bind to the cell wall, along with two other chemical modifications that might reverse an enzyme or affect the cell membrane. This is interesting for those in chemistry, but the upshot is that, at least in vitro, there is about a 200-fold improvement in vancomycin activity against VRE with minimum inhibitory concentrations as low as 0.005 µg/mL against that organism. This makes you think that you could use far less of the drug, and therefore perhaps avoid toxicity issues, if indeed this drug proves to be safe upon additional testing.

Another drug, fusidic acid, has been used in Europe for over 40 years and is available in oral or IV formulations in many countries. It has little cross-resistance to other bacteria and is predominantly used for staphylococcal infections. However, resistance to fusidic acid develops rather easily, especially with significant infections with high organism counts, which means that often it was combined with a drug such as rifampin. A new frontloading strategy may mean that it has a new life as monotherapy and is currently being explored by the pharmaceutical industry. We will see if it gains FDA status for use in the United States.[4]

Many have already taken to fosfomycin salts for use of resistant gram-negative infections for urinary tract infections. They even try to use high doses of fosfomycin daily, or even at higher doses, to treat other resistant infections. There are other agents not available in the United States any longer, such as mecillinam or temocillin, that are used in other countries for Enterobacteriaceae infections.[5] I've had two patients with very resistant infections, where I really didn't have any other oral agent. Rather than admit people to the hospital, I used cycloserine, normally reserved for tuberculosis.[6] In the 1960s, the drug had been used for urinary tract infections and indeed is still licensed in several countries. Only one or two patients really responded successfully.

Again, I think we are dusting off all drugs, trying to improve on some of the drugs we have, tinker with them. This may be a bit of a faster path, at least in some cases, than trying to find new and novel compounds in the current climate. I hope many of these efforts, of course, might help us take care of patients with resistant infections. You can see that with the scarcity of new agents, a lot of bright ideas are being entertained.


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