It's the Resistance, Stupid!

This is not the MRSA pandemic, ladies and gentlemen. Lets take a look at the MRSA pandemic. In  US hospitals, even today (latest CDC data is from 2014), 46% of S. aureus IV catheter, urinary catheter and surgical wound infections are MRSA. At one point, in the early 2000s, over 70% of S aureus isolates from emergency rooms in the US were MRSA. Although the resistance levels vary from state to state, the range of MRSA is 33-68%. 

Looking at the same CDC data set for carbapenem-resistant Enterobacteriaeceae, for example, we can see that the US average is about 3.5% and ranges from 0-12%.  The state with 12% levels of resistance is New York, by the way. As of five years ago, there was, therefore, over a 10-fold difference between the incidence of CRE and MRSA infections that are followed by the CDC. 

If we now apply these data to US market conditions for antibiotics, the comparisons become enlightening. The MRSA pandemic started in 1968 and accelerated around 1982 or thereabouts. By 2005, over 50% of S.aureus isolates in US hospitals were MRSA. To translate that into actual infection incidence rates, see the figure below from the CDC. In 2005 there were almost 20 MRSA infections per 1000 hospital admissions. Although this number has decreased, as noted above, 46% of strains are still MRSA. 

This tremendous medical need drove the market for anti-MRSA drugs for years.  Incredibly, the only (mostly) drug available to treat serious MRSA infections was vancomycin.  The graph below shows how this market was driven in terms of annual production of vancomycin by Lilly. The market continued to drive the sales of newer agents like linezolid and daptomycin.  Whether that will apply to newer anti-MRSA agents is not really clear. 

I have been unable to find US case incidence rates for CRE infections. But clearly, this is not the MRSA pandemic. For MRSA infection, we always had vancomycin, and later there was linezolid and daptomycin. Of course, before 2015 and the approval of ceftazidime-avbactam, there was almost no therapy for many of these resistant Gram-negative infections.  With emerging resistance to the polymyxin, there was no therapy at all.  Now, of course, we have ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, and plazomicin. With the possibility to combine aztreonam with any of the above, the truly untreatable infections are exceedingly rare today. 

Resistance is spotty. If you are hospitalized in New York and you acquire a Gram-negative infection in hospital, there is a reasonable chance it will be caused by a highly resistant pathogen. If you go to a hospital in New Hampshire or Vermont, there is almost no chance for that to happen. Even within New York, there is considerable variability from hospital to hospital and between geographic areas. My recent survey on the utility of reimbursement rates for expensive new antibiotics active against these resistant Gram-negative pathogens reminded me of the spottiness of this resistance.  Those centers that already have a significant resistance problem are already using the expensive drugs with little thought to their expense.  They understand that efficacious, non-toxic therapy of serious infections is always cheaper than non-efficacious toxic alternatives. Those centers that simply do not see resistance, or only see such cases very rarely, have not considered adding these new drugs to their formulary simply because they do not need them.  In my survey, price seemed to be of little concern. But something must account for the fact that about 35% of CRE infections in the US are still treated with the polymyxins (see this paper by Clancy et al).

The problem is, though, that resistant Gram-negative pathogens are unlikely to go away, and are, in fact, more likely to spread. And, not only that, but as Stuart Levy would have pointed out, resistance to the new antibiotics will also crop up. To deal with that, we will need to use the newer drugs we already have and we will need a pipeline of new antibiotics for the future.  Not only will we need antibiotics to overcome emerging resistance, but we will need a choice of various classes to provide alternative therapies for drug intolerance and for specific types of resistance. But today, because of the lack of a sufficient level of resistance to drive appropriate use, the market simply does not exist. And without the market, there will be no new drugs. 

So – what we need to do is to establish a market in the absence of a medical need that is sufficient to drive the market by itself. We also need to recognize that this is what we are asking. Yes – there is a resistance problem. Yes, there are more and more serious infections that are “difficult to treat.”  And yes, there are areas where these infections are common like Greece, Italy, and New York. But all this together, as yet, does not a market make. What we don’t want to do is wait until there are sufficient numbers of highly resistant infections to drive the market. This will be especially true if resistance to the newer drugs emerges – because then it will be at least a 10-15 year wait for new, effective antibiotics. 

Stuart Levy - A Giant in the Fight Against Resistance is Gone

Stuart Levy passed away last week after a long illness.  He was a friend, not a close friend, and a colleague.  I hadn’t spoken with him in a while – probably not since I wrote an article for the Alliance for the Prudent Use of Antibiotics (that he founded) Newsletter last year. But I think I speak for many when I say that I will miss Stuart. 

I first met Stuart in the mid-1980s, just after I started my career in infectious diseases. He was one of a number of antibiotic-resistance researchers who were complaining that the NIH was not funding their research. I joined this group of “disgruntled” scientists, as Science magazine referred to us in a 1994 article, and got to know Stuart well.  He was a leader of our effort to try and hold the NIH accountable. We felt that our grant requests were not being reviewed by our peers, but rather by experts in areas such as vaccinology, immunology and pathogenesis. Our group included greats in the area like George Jacoby, Bob Moellering, Gordon Archer and several others. Stuart was instrumental in getting the NIH to provide data on their past funding for antibiotic research (nil) and for helping to arrange a series of workshops with NIH to explore the reasons for this lack of funding and lack of appropriate peer review. He was the diplomat of the group. The NIH finally followed Stuart’s advice and established a separate study section to deal with antibiotic research 20 years after Stuart first suggested the idea.  

When I met him, Stuart corrected my misguided assumption that he was a microbiologist or an infectious diseases specialist.  He pointed out that he was a hematologist in a department of hematology and oncology. I understand my mistake as I look back on his career. He was probably the first or one of the first to demonstrate the effect of antibiotic feed supplements for animals on the emergence of resistance in farm animals and the transmission of that resistance to humans in the farm environment. He developed the notion that antibiotics follow the “you use it, you lose it” rule, and that using them more sparingly might delay the emergence of resistance.  He was a strong believer in the idea that the density of antibiotic use was correlated with the rapidity of emergence of resistance. He founded the Alliance for the Prudent Use of Antibiotics in 1981 with the goal of protecting that precious resource. 

In the late 1990s, Stuart was part of a large group working on guidelines for the Infectious Diseases Society of American and the Society for Healthcare Epidemiology of America for the prevention of resistance in hospitals. This turned into a two-year effort where I became the secretary for luminaries like Stuart, Dale Gerding and John McGowan. Stuart and the others pushed hard for systems to control the use of antibiotics in hospitals with the goal of slowing emerging resistance.  In the guidelines that were finally published, this became known as antimicrobial stewardship and achieved prominence both then and now. 

Stuart also pointed out the potential importance of antibacterial products used in homes and industry for everything from hand washing to environmental cleaning. He realized that resistance to these products was often related to augmented bacterial efflux, and that this efflux could affect the activity of standard antibiotics as well. 

In later years, I used to quibble with Stuart by noting that even appropriate use of antibiotics, as is the case for most hospital use these days, will select for resistance. He would always counter with his density of use argument. 

Stuart also was prominent in showing us that commensal bacteria could be important harbingers of resistance genes for pathogens.  Thus, antimicrobial use of any kind could provide selective pressure on the commensal flora that, in turn, could pass on acquired resistance determinants to any pathogens in the same niche. He noted that the problem was that we did not routinely survey these commensals, but rather focused on the pathogens. 

Stuart was a tetracycline researcher.  Not only did he discover various tetracycline resistance determinants, but he also founded a company (Paratek) that competed with Wyeth in the development of new tetracycline analogues.  I remember this well since I worked at Wyeth where tigecycline was our major project at the time. During Stuart’s work on tetracycline resistance, he came upon the Mar system that was involved in the early steps towards multiple antimicrobial resistance as well as being important in virulence and the response to environmental stress in bacteria. 

I always considered Stuart a friend and a mentor. I am personally saddened by his passing. There are few with the depth and breadth of knowledge combined with an ability to move others to act that Stuart possessed. We will all miss him.