Antibiotics - Innovation or Clinical Utility?

Lately I have become intrigued with the word, innovation. Innovation is used a criterion for funding grants, for status in reviews of our antibiotic pipeline, for intelligence, imagination and many other great things. I want to explore the meaning and utility of innovation in the particular context of antibiotic discovery and development and of our antibiotic pipeline.

A story I tell frequently comes from my days as a practicing infectious diseases physician at the Cleveland VA Medical Center. In the early 1980s our surgical ICU suffered an outbreak of bacteremia and pneumonia caused by Serratia marcescens resistant to all the antibiotics we tested at the time (colistin was not on that list). But imipenem was undergoing its phase 3 testing and I was able to obtain some under a compassionate use protol that Merck had established. I am sure that we saved lives. But imipenem is really just a B-lactam – albeit a very special one.  Is it innovative? I think so.  But more importantly, its clinical utility was infinite for the care team and our patients. 

To me, innovation stands for imagination, daring, intelligence and the ability to see things beyond what we know and think we understand. To innovate is to navigate to where we have not gone before, and, hopefully, to see a way to get there. So, yes, innovation can be a good thing. In the context of antibacterial discovery, Theuretzbacher et. al. note that for many, innovation connotes a novel target or novel chemistry or novel mode of action. In the end, Theuretzbacher et. al. end up defining innovation as simply meaning that the therapy shares no cross resistance with existing therapies. 

I would like to introduce a more useful concept – clinical utility. Clinical utility clearly would include a lack of cross-resistance, but also may include other advantages.  A new therapy might avoid the need for monitoring drug levels, it might be more safe than existing treatments, it might reduce the numbers of doses required, it might be orally bioavailable, or it might avoid the need for new, experimental diagnostic tests. All of these speak to the utility of any new therapy to the physicians who prescribe it and the patients they treat. 

In my world, innovation also means risk. And risk in the pursuit of new and important therapies is fine as long as everyone understands that this is the case. Therapies directed at novel targets, those that use novel chemistry and those that exploit new modes of action all are subject to increased risk.  The risks include the risk of scientific failure early in the discovery process, the risk of failure from non-clinical safety studies and the risk of clinical failure either because of safety or efficacy issues. 

On the other hand, the use of known targets, known chemistries and known modes of action reduces risk. Sometimes, this lack of “innovation” might also lead to a lack of clinical utility.  But, historically, while this does occur, there have been many very useful but not so innovative therapies to come forward over the last several decades. The B-lactamase inhibitors recently introduced to market (avibactam, vaborbactam) have a much broader spectrum of inhibition than their predecessors. They are innovative in that they utilize new chemistries to achieve their improved spectrum. Of greater importance to me, they have increased clinical utility based on this broad spectrum of activity and still avoid most cross-resistance. A major addition to our clinical armamentarium will be aztreonam-avibactam that will have activity against Class B B-lactamases, a group of enzymes that have so far eluded the BLI-BLA strategy. At this point, one could argue that this combination is not so novel or innovative and that would be true.  But look at how clinically useful it might be. Another pipeline combination that achieves this goal is VNRX5133-cefepime from VenatoRx. In this case, the inhibitor is still based on boron chemistry like vaborbactam, but is able to assume different binding modes to inhibit class A and B B-lactamases – an innovative mode of action.

When I look at drug discovery and development plans and proposals, although I consider “innovation,” what I truly evaluate and value is potential clinical utility. These two characteristics do not always go together. I suggest that we all prioritize providing better (but not necessarily innovative) therapies to our patients with unmet medical needs as our ultimate goal.

The CDC's Report on Antibiotic Resistant Threats in the US

This is Antibiotic Awareness week. The US Centers for Disease Control just released their new report, Antibiotic Resistant Threats in the United States, 2019. They used “new” methodologies to both retrospectively reconstruct their 2013 report and to carry out the studies used for the 2019 report.  In that way, the numbers are directly comparable. This report is extremely valuable and I recommend it as required reading for everyone interested in infectious diseases and antibiotics. 

While this new report is very welcome and while I (and everyone else) appreciate(s) all the efforts by the CDC to address resistance, there are still limits to the report and areas that I would have liked them to address differently. First, the numbers cited by the CDC must be considered an underestimate since they are derived almost exclusively from hospital data.  There are probably many infections arising in the community that do not present to acute care hospitals including those in long term care facilities. Second, I would have preferred that the CDC emphasize more that in spite of all of our efforts, no matter how successful, at antimicrobial stewardship and infection control, resistance will still emerge and we will still need to rely on new antibiotics to control these resistant infections. As such, additional discussion as to the factors combining to deprive us of these needed new antibiotics and suggested approaches to resolving this dilemma would have been helpful.

If you add the numbers for C. difficile infections to those for other resistant infections together, the CDC reports that there are ~ 3 million such infections per year in the US.  These are associated with almost 48,000 deaths every year.  These deaths approach that endured by the US military for the entire Vietnam war (58,000) and are greater than the numbers of Americans killed in traffic accidents every year (37,000).  The CDC provides data for certain resistant infections (see report) showing that they place an important economic burden on US healthcare. The CDC appropriately notes that antibiotic resistance threatens our ability to provide adequate care for surgery, chronic conditions like diabetes, organ transplant recipients, kidney dialysis patients and those with cancer.

In its report, the CDC emphasizes that they are leading the fight against resistance and, in some cases, we are making progress. For example, infections caused by carbapenem-resistant Acinetobacter have decreased since 2013.  But infections caused by carbapenem resistant and ESBL Enterobacteriaceae have increased.  In long term care, C. difficile infections may be decreasing, but we have not yet seen that in US hospitals. 

While the CDC emphasizes approaches like vaccination, infection control, antibiotic stewardship in hospitals, in the community and on our farms, and while they note that antibiotic resistance is a one health problem, they shy away from the economics of antibiotics. They do not deal with the important role that expert societies can play in guidance on all of these issues, but, importantly, a discussion of their role in assuring appropriate therapy is not really explored. 

The report outlines some of the difficulties in the development of antibiotics and diagnostics and it also decries the poor pipeline for many of the resistant infections considered as threats in the report. They believe that there is not enough “innovation” in the pipeline. 

In terms of innovation, I note that the WHO and others also see this as a problem in the antibiotic pipeline.  I strongly disagree with the concept that innovation is the most important criterion by which to judge the pipeline.  The most important criterion should be clinical utility.  Does the compound address resistant infections?  Is it safe?  Does it offer dosing or other advantages over other available therapies? (This will be the subject of a subsequent blog).

One area that CDC ignores is the economic barriers to the study and marketing of new antibiotics. The report sticks with the steps that we should all be taking to preserve the antibiotics that we have as long as possible.  And I agree that this is an important effort that we all should support. But, if the CDC leads the fight against resistance, they can hardly step back from dealing with the single major impediment to providing the robust pipeline they so clearly desire. To me, this is a singular omission in this otherwise complete and important document. 

The Echo Chamber

I just finished writing a commentary for Antimicrobial Agents and Chemotherapy entitled, The Economic Conundrum for Antibacterials. You can find the accepted manuscript ( requires subscription) here.  Earlier this fall, I was interviewed for a podcast – you can listen here. In both cases, I argued that the numbers of patients with highly resistant infections today are not sufficient (in the developed world) to drive an adequate market for antibacterial drugs active against these resistant pathogens.  I made the point that our pipeline is precarious. Next I tried to show how the economics of commercialization of new antibacterial drugs put companies, especially the small companies that provide the bulk of our antibacterial pipeline today, in the crosshairs of financial failure such as occurred with Achaogen. 

Both during the podcast interview and in the review of the manuscript, I was confronted with what seems to be a dominant view outside of our own echo chamber. That view is that the market is not failing – it is working and telling us that there is just not a sufficient medical need today and that it is not guaranteed that the need will be there in 10-20 years. 

The reviewer provided additional feedback that I will try and summarize. 

They noted that even though the pipeline might be considered to be inadequate by us “experts” it is more robust today than it has been at any time since the 1990s. And, I admit, that is true.  But a careful look at the pipeline reveals a number of substantial weaknesses that did not exist in the 1990s.  First, the majority of the sponsoring companies are small biotechs with precarious financing. Second, many of the pipeline products, especially those in preclinical and early clinical development are very high risk. I still believe, therefore, that the pipeline is not going to be adequate if resistance to current first line therapy continues to grow and especially if resistance to second and third line therapies emerges and grows rapidly. 

The reviewer also was of the opinion that Achaogen got what it deserved. He argued that they sunk a great deal of money into a product the market for which was probably not what they advertised.  And they were critical of Achaogen’s investment in discovery research. 

The reviewer was also apparently upset that much of the small molecule pipeline today consists of “me too” products including Achaogen’s plazomicin. My view is that one person’s “me too” is another’s best friend. But it is clear that for plazomicin, the projected medical need and market were just not there. 

In my paper, I spent time reviewing post-approval activites that companies undertake and their costs.  Some of these are required by the regulatory authorities while others are more focused on education and “marketing.” The reviewer noted that no company should commit to exorbitant post-approval obligations for a product with a very limited market. 

Finally, I was accused of being an investor in the industry who is just out to make a “tone” of money. 

While it was difficult for me to read the review of my paper and, at times, to hear the podcast interviewers’ views, the experience was eye-opening.  I find that us “experts” spend a great deal of time talking among ourselves in a sort of echo-chamber bubble that protects us from these opposing views. And I see that these views are not necessarily those of a small and radical minority, but probably represent a far more substantial set of clinicians, pharmacists and other stakeholders. 

One area where everyone seemed to agree (whew!) that action was necessary was at the level of expert societies and automated susceptibility testing devices.

·      I suggested that that expert societies step up to the plate and provide a minimum of yearly update on suggested therapies for key infections; 

·      And that automated susceptibility testing kits be required to provide clinical laboratories with testing capability for such new, high priority drugs within one year of approval. 

After all this reflection, though, I find myself back at the starting line. What will we do today to deal with a future of uncertain rates of bacterial resistance? Will we act to protect investments in important potential antimicrobial treatments or will we let market dynamics take over? 

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.

Incentives from Medicare?

The key problem for many struggling with the treatment of resistant infections and a paltry pipeline of new antibiotics has been the lack of a return on investment for companies trying to discover and develop new antibiotics.  In hospitals, since these infections may be rare for a given center, there is a reluctance to place expensive new antibiotics on formulary and stock them given a limited pharmacy budget. This may result in a delay in adequate therapy or the substitution of older, cheaper and toxic drugs like colistin for newer, more expensive, more effective and less toxic therapies like ceftazidime-avibactam.  This concern is borne out by market data on antibiotic use in the US. 

Recently the Centers for Medicare and Medicaid Services (CMS) launched policies meant to provide incentives for hospitals to use newer, expensive, more effective and less toxic antibiotics for the treatment of infections caused by resistant pathogens. Obviously, this will only apply to the US. CMS provides a two-pronged approach. Hospitals can now apply to receive reimbursement of 75% of the drug cost beyond the usual diagnostic related group (DRG) reimbursement. The previous reimbursement allowed being only 50% under their New Technology Add-on Payment (NTAP) program.  (The DISARM bill currently under consideration in congress would allow a 100% reimbursement for drug charges for the treatment of resistant infections – but I am not sure if that would have to go through the NTAP application procedure or not). In addition, hospitals can now classify resistant infections under CMS’ “complicated conditions” rubric allowing for a higher reimbursement than would be obtained under a usual DRG. For a more complete review of this, see this article.

Lots of really smart people are very excited about these new “incentives.” Either I’m not so smart or someone is out of touch with reality. Being a data-driven person, I reached out to five hospitals.  Four are large, academic, multi-hospital groups.  One is a small hospital that is part of such a group but that functions semi-autonomously. People I contacted included a CMO (Brad Spellberg of USC), two antimicrobial stewardship directors, a pharmacist and an infection prevention director. OK.  This is not an extensive survey, but so far the response has been unanimous.

I posed two questions.

1.  Will these (new CMS moves) measures make any difference to formulary position or prescribing patterns in your hospital?

2. If there were 100% reimbursement instead of the 75% CMS currently proposes for expensive antibiotics and as described in the DISARM Act before congress, will that make a difference?

I have received four responses – all from large centers.  All stated that the new CMS incentives would NOT change current practice in their institutions. Only one center stated that if they consider placing the new expensive antibiotics on their formulary, these incentives would help their argument to the hospital administration.  Currently, their resistance rate is so low that they haven’t considered it necessary to have these drugs on their formulary (see below). 

1.    Resistance in two of the centers I polled is rare.  This is consistent with a recent study of “difficult to treat” infections in the US where only 1% of bacteremias caused by Gram-negative pathogens were considered to fall into this definition. Resistance across the US is spotty.  The latest CDC geographic data is old and comes from 2011-2014 and can be seen here.  But for these centers, there is no urgency to place newer agents on their formularies.

2.    In several centers, the antimicrobial stewardship group and/or individual physicians are given considerable autonomy in prescribing and the expensive new drugs are already being used in the absence of any incentives. 

a.    This suggests that the rarity of resistance is more important in determining the market than the expense of new drugs in many centers. 

b.    Physicians generally have no idea what DRGs or CCs are nor do they know about the costs of antibiotics.  They prescribe drugs targeting their individual patients’ needs without considering DRGs or other administrative issues.  

3.    The NTAP application process is burdensome and many hospitals hesitate to use it for that reason (as I’ve heard from previous inquiries). 

4.    One center is skeptical that the complicated condition reimbursement will fully cover their costs for resistant infections. (But I would think that any additional remuneration would at least be an improvement)

5.    In the case of Brad Spellberg’s hospitals at USC in California, 80% of their patients are covered by MediCal, not Medicare.  So these incentives would not apply to them anyway.  Others note that private insurers might not follow CMS’ lead here either. 

I am convinced by the market data that patients are still being treated with colistin/polymyxin in lieu of new antibiotics.  I think this is partly because expensive newer agents don’t get on hospital formularies. If higher reimbursement will encourage some hospitals to change their approach in a positive way, that would be great.  But the responses to my small survey were not terribly encouraging in this regard. 

CMS is to be commended for trying to address the antibiotics market failure by providing policies meant to incentivize appropriate use of newer antibiotics in spite of their expense. Nevertheless, based on the responses I received, it is not at all clear that the CMS incentives will significantly increase formulary inclusion of the newer antibiotics or their use by physicians – therefore, it is not at all clear that these moves will work as intended by CMS.  As Brad noted to me, it seems like CMS and the pundits advising them failed to actually speak to physicians and pharmacists on the front lines to understand what might and what might not work. 

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My view remains that in order to fix the broken antibiotic market we will need a very significant pull incentive such as a market entry reward or a transferable exclusivity voucher. 

Expert Societies Need to Step Up

I have a modest proposal that comes from my recent discussions with Brad Spellberg, Lew Barrett and John Rex. I am grateful to all three of these experts for their thoughts on this topic. 

To successfully commercialize a new antibiotic, the drug must be shown in clinical trials and via microbiology and PK/PD data to provide advantages that fill a medical need.  An obvious example would be if someone markets an oral antibacterial active against MDR pathogens that works clinically in complicated urinary tract infection. The “educational” activities (marketing) required to convince physicians and pharmacists that any new agent should be available to physicians via their hospital formulary or that insurance companies should cover the cost of a new drug in community pharmacies, requires a substantial investment by the company.  For a hospital product, I have heard cost estimates from $8 million for a single-indication drug to $30 million for one with multiple approved clinical indications. For a community-based product, this cost could be much greater given the number of physicians, pharmacies and insurance plans one would have to inform. 

A number of small companies have drugs in the pipeline in phase 2 or later development.  They will all be severely challenged to meet the costs of launch if these drugs are actually approved for the marketplace.  A substantial number could face bankruptcy just like Achaogen.

My proposal is that the various societies that promulgate authoritative clinical guidelines intervene either at the time of approval or simply on an annual basis to disseminate key educational information and very focused real-time clinical guidance as to how the new drug should be used. Every guideline has a table summarizing recommended therapies for the clinical indication under consideration.  It is this table that could be targeted for modification.  By focusing on just the therapeutic recommendations portion of the guideline, the task for societies should be less burdensome that a review of the entire guideline. These societies might include the IDSA, ATS, BSAC, the Society of Infectious Diseases Pharmacists and others. I am not sure how much this would affect initial expenses associated with launch, but it should accelerate uptake of deserving therapies. 

To achieve this, sponsors would need to provide a full package of clinical trial, PK/PD and clinical microbiology data to the societies in a timely manner. I suggest that this would occur after the regulatory interactions that lead to approval.  In this way, regulatory feedback can also be included in the information provided to the societies. Sponsors should also provide a preliminary price estimate to the societies. The societies would then modify (or not) the table of therapeutic recommendations in clinical guidelines for physicians. The societies would, of course, be free to provide additional details in guidelines that might expand on the table or even limit the use of the new drug based on their view of cost, side effects, toxicity and benefits compared to products already available. Of key importance would be to place the new product in the context of older therapies.  (I have colistin and polymyxin firmly in my sights here). The sponsors would not pay the societies for this work. But, of course, sponsors would be free to disseminate any modified guidelines resulting from the societies’ work.

The societies, especially the ID pharmacists, should also consider making recommendations regarding off-label use.  These should be based on clinical (if any), microbiological and pharmacodynamic and pharmacokinetic data. 

An example would be guidelines including a treatment recommendation table. This guideline should have been promulgated within a year after the approval of ceftazidime-avibactam.  It might have discouraged the use of colistin or polymyxin for the treatment of resistant Gram-negative infections and encouraged the use of the newer, albeit more expensive, agent for cUTI, cIAI, and nosocomial pneumonia when resistant pathogens susceptible to ceftazidime-avibactam were suspected or documented. 

I think that we can all agree that timely modification of guidelines from experts would go a long way towards modifying the treatment paradigms utilized by physicians.  If you have any doubt about this, look at the effect of a recent guideline change on the use of fidamoxcin in the treatment of C. difficile. Its shameful that it took eight years to get to this guideline change. Our expert societies simply have to do a better job of keeping up with the changing therapeutic environment as resistance evolves. Such action would, in a modest way, provide an additional pull incentive for sponsors and investors.