Superbugs, Antibiotics and Drug Safety

I’m back.  Vacation was great.  Now I’m being punished for having taken one. Oh well . . .

Well, NDM-1 has arrived in the US.  These Gram-negative bacteria cause everything from urinary tract infections to brain infections and pneumonia.  The can be treated, usually, by only one or maybe two antibiotics, and sometimes, by none. Of course, as noted in previous blogs, KPC-2 bearing Gram negative bacteria have been here for a long time and have already invaded 35 states that we know about.  Since we do not carry out active surveillance, what we know about these resistant bacteria probably only represents the tip of some undetermined iceberg. A recent report on CBS News shows the devastation these infections can wreak on patients and families to say nothing of their physicians struggling to treat what used to be a fairly simple infection in days gone by.

Of the 90,000 deaths occurring due to infections acquired in US hospitals every year about 70,000 involve antibiotic-resistant bacteria.  These numbers do not reflect resistant infections acquired outside the hospitals which may be much more frequent if sometimes less serious.

With serious infections caused by bacteria that are more and more resistant to the antibiotics we have in our armamentarium, we still face enormous roadblocks to the discovery and development of the new, effective antibiotics we need now.  Our need for new therapies is likely to become desperate in the near future if we don’t act now.

The FDA is entrusted with ensuring that the drugs that are marketed in the US are safe and effective.  But these terms are relative.  The question is, to what extent must we go to prove sufficient safety and efficacy for the treatment of which infections?  The more serious and life threatening, the more we can tolerate adverse events as long as we can pull the patient through. But what about efficacy?  How can we prove efficacy is these patient populations?  They are the hardest to actually enroll in trials because they are so ill.  The results of therapy are frequently hard to interpret because they are so ill.  Is the fact that they survive enough?  Can we compare such patients to historical controls?  How good would the database of historical controls be for KPC-2 infections since this superbug has just emerged on the scene recently, and since there are sometimes at least one or two presumably effective antibiotics left to treat it. For example, lets look at NXL-104 – ceftazidime, a combination of a resistance inhibitor (NXL-104) and an antibiotic that is already marketed that is being developed by Astra-Zeneca. NXL-104-ceftazidime is very active against KPC-2 bearing Gram-negative bacteria. For patients with such infections where there are few if any other choices, is it ethical to withhold what will very likely be effective therapy?  We can predict efficacy for antibiotics so well using preclinical models that many would argue that it would be unethical to withhold such potentially life-saving therapy under these circumstances.  But would the FDA approve, at least conditionally, an antibiotic developed in this way?  Since, presumably, only a small number of patients might be studied – perhaps in the low hundreds, what do we do about a database to establish safety?  These are all questions being debated and discussed by the FDA, industry, the Infectious Diseases Society of America and others. 

A decade ago, Mark Goldberger, when he was Director of the anti-infectives division at FDA, called for high quality studies using a small quantity of seriously ill patients in trials of antibiotics. In the decade that has passed since then, we have rolled backwards in our ability to streamline and improve the relevancy of antibiotic development.  Companies are dropping out of the field right and left.

One major point that must be considered in all of these debates is – a lack of new antibiotics active against key resistant strains is, itself, a safety issue.  The FDA must recognize that acts of omission might also be important contributors to a safety risk for the population.  This key ingredient must be added to the stew of strategic thinking on antibiotic development if we are ever going to get anywhere.