Antibiotic Discovery: Two Steps Back?

This didn't take too long...

We've written often about the need for new antibiotic classes, so called antimicrobial discovery. Over the past 3-4 years there have been significant US efforts and European efforts to expand the search for novel antibiotics. Well, as they say, two steps forward and one step back.

The Boston Business Journal is reporting that Merck is closing Cubist's entire 120-person early drug discovery unit. Per the report, "Merck remains committed to the development of antibiotic drugs, and an unspecified number of drugs still in pre-clinical testing will continue development in other sites. All of Cubist's drugs in clinical trials will continue to be developed."

On the other side, Derek Lowe over at Seeking Alpha - a crowd-sourced financial site - writes: "So anyone who thought that this might be about some sort of long-term commitment to antibiotic discovery, well, think again. This is about getting Cubist's existing drugs, back to some unspecified point in development, but the discovery work gets raked off into the compost pile."

I suspect many others will be upset with Merck's move. Given the oversized role that Cubist has played in antibiotic discovery recently, the unit's closure is frustrating. Where will new antibiotics come from if large pharmaceutical companies do not invest in novel antimicrobial discovery? Maybe they just aren't the right place.

Antibiotic Resistance - A Global Problem

Today, The Lancet Infectious Diseases Commission on Antibiotic Resistance led by Otto Cars from the Swedish Institute for Communicable Disease Control has published "Antibiotic resistance—the need for global solutions." The stated goal of this 42-page tour-de-force is to "explore why antibiotic resistance has become such a problem worldwide, and, most importantly, propose solutions to avert the impending crisis."  The Commission is broken down into nine parts with each group of authors responsible for their individual sections. I've pasted the table of contents to the right (click to enlarge). The document discusses antimicrobial use in humans and animals including stewardship, improved diagnostics (hopefully Dan will comment on part 3), novel therapeutics and antibacterial drug discovery.

The Commission is accompanied by 7 commentaries from the global community, which are each worth a read. All articles are free to access once you set up a username and password.

These documents are largely focused on antibacterial use and development, which are incredibly important global problems that will require collaborative responses at the local, national and international level.

But much like the recent Frontline documentary that, as Dan mentioned, did not have "enough discussion of the hard work of basic infection prevention," infection control is only briefly mentioned in the main document. (Section 2, page 7) You can get the sense of the Commission's approach with this quote: "From a resistance perspective, prevention reduces antibiotic use and the spread of resistant bacteria; however, prevention is not the main strategy to control resistance because antibiotic use also needs to be controlled."

Of course, "benchmarking (open comparison of health-care facilities) of frequencies of health-care-associated infections is useful." Yet public reporting is only useful as far as we have effective methods to prevent the reported infections.

Despite these minor quibbles, this is an incredibly timely and tremendously useful report. The authors and the Journal should be congratulated. Let's hope it moves the needle towards more recognition and funding for antimicrobial discovery, antibiotic stewardship, and perhaps... infection prevention?

Antibiotic Discovery: Focusing on supply while ignoring demand is doomed to fail

There is an article in today's New York Times (above the fold on page one - see image) that brings the problem of antimicrobial resistance and antibacterial discovery to the public's attention. It's a very important issue and many of the points raised in the article are spot on. Just some things for you to think about when you read the article:

1) Health and Human Services is giving between $40 and $200 million to GlaxoSmithKline over the next 5 years for drug discovery. This amount approximates what NIH spends on all antimicrobial resistance research for ESCKAPE pathogens ($50 million annually).  It's surprising that this amount couldn't be targeted to NIH or CDC funding instead (or ever).

2) Frustratingly, there was not one mention of antibacterial stewardship or infection prevention. Back when I was studying economics under this guy at University of Michigan, I learned about price determination. In principle, the price for a good will tend to settle where demand equals supply. I think of antimicrobial resistance the same way - demand is the need for broad-spectrum antibiotics based on resistance levels in the community and supply is the availability of effective antibiotics to treat resistant infections. If we focus on the supply side by funding pharmaceutical companies, we may end up with more effective antibiotics, but the set point equilibrium with high levels of resistance will remain if we continue to ignore the demand side.  To fix the demand side we need equal investment in stewardship and infection prevention research and implementation. Give $200 million to prevention research and we might actually find ways to scientifically achieve hand hygiene compliance over 50% without just yelling at health care workers! Imagine that...pause...

What did grandma tell me when I was little? - "an ounce of prevention is worth a pound of cure." I think she was spot on and it's is probably why I became a hospital epidemiologist. Thanks grandma.

Europe boosts antibacterial discovery funding from zero to a wee bit more than zero

This week's Lancet has a report on a new European public-private partnership called the Innovative Medicine's Initiative (IMI). The IMI is funded through €1 billion donations from both the EU and European Federation of Pharmaceutical Industries and Associations to stimulate innovation in challenging areas. The goal is to fund antimicrobial drug discovery to the tune of €600 million ($761 million) by 2020, or roughly $100 million/year.

Perhaps this is finally the chance to move beyond the two new classes of antibacterials developed in the past 30 years. Should we be excited? Sure, $100 million/year seems like a lot of money, but this should be seen as a necessary first step.

First, this $100 million has many targets including MRSA or Acinetobacter and if you think about the way NIH defines antimicrobial resistance, most might go to non-bacterial pathogens. Second, when you compare it to the funding spent confronting a single viral pathogen, HIV, it quickly becomes clear that more is needed. For example, NIH spent $3.075 billion on HIV/AIDs research in FY12 and expects to spend the same amount in FY13. Thus, if we assume flat budgets, that would be roughly $23 billion by 2020. $23 billion is 30 times $761 million. Exactly. Well, not exactly, but you get my point.

image source: http://prospect.rsc.org/blogs/cw/2010/02/26/chemistry-worlds-weekly-round-up-of-money-and-molecules-107/

Orphan-drug funding crowding out antibiotic discovery?

There's an interesting story today by AP Health writer Matthew Perrone that delves into reasons why little is spent on antimicrobial drug discovery in the US.  His hypothesis is that funding for orphan drugs is crowding out antibiotic drug discovery in the private sector, forcing the US Government into action.  The evidence offered is compelling, including the fact that 11 of the 30 new drugs approved last year were for rare medical conditions, the highest level since FDA incentives began about 30 years ago. These incentives include extra patent protections, higher pricing and a streamlined FDA review. The results speak for themselves: the first new SLE therapy in 50 years and first new Hodgkin's therapy in 30 years.

However, the evidence that this is actually spurring US-government funded antimicrobial drug discovery is weak.  We're offered the somewhat misleading fact that "since 2006, government spending on research for familiar diseases like staph infections, smallpox** and botulism** has increased more than 660 percent, from $54 million to $415 million last year." OK...so what does this have to do with antimicrobial discovery?

To further highlight the dearth of investment in antibiotic discovery, we have this quote from Dr. Anthony Fauci: "We have pushed the envelope more toward diminishing the risk for companies so that they'll be more interested in getting involved with us and developing things like vaccines and antivirals." To be fair, he cold be talking about the mythical Staph vaccine. But seriously, whatever happened to "eschew obfuscation, espouse elucidation"?

The rest of the article highlights new investment in therapies for tularemia and agents of bioterror and new flu-vaccine manufacturing techniques. I had my hopes up for a minute.

**Note: There are on average 110 cases of botulism in the US every year and zero cases of smallpox.  This compares to 19,000 DEATHS from MRSA per year, which would be at least twice that high if we included MSSA. Familar does not equal common.

Source: Matthew Perrone, SFGate (AP) 1/25/2012

Deus ex machina and antibiotic resistance

Last night, I watched a movie with my young kids. The "plot" involved friends traveling with one of their moms to Japan and then getting lost.  It was a bit scary for my kids. I was even a bit worried, since I had no idea how they would ever be found, but this was a Disney movie, so I knew it had to have a happy ending. Just when it all looked lost, the mom realized she had placed a tracking device under her son's skin when he was a baby and she also happened to have the required GPS tracking device in her purse.  Boom! Kids found, all was well. Ridiculous. Sure, my kids were happy, but where is the lesson there?

Flashback to a conversation I had three weeks ago with a visiting professor in general internal medicine.  She is a very well-known clinical researcher in oncology, an area that is well-funded unlike antibacterial resistance, and I wondered what she thought of the lack of new antibiotics in the pipeline, the rise of novel resistance mechanisms in Gram-negatives like NDM-1 and how she thought this would impact oncology.  Her response? Her jaw dropped.  She thought that there was always another antibiotic in the pipeline or in the ID physicians back pocket to pull out and save her patients. It had actually never occurred to her that we have had close to zero new classes of antibiotic in decades.  It was like life was a Disney movie and we could just pull a new antibiotic out of the air to save the day. Ridiculous.

But, whose fault is that?  I don't think it is the oncologist's fault. Is it the ID physician's fault who always sounds so smart and attempts to prove her usefulness by pretending that a polymixin is a useful new antibiotic! Is it the funding agencies that have ignored bacterial infections since the 1960's and certainly since the 1980's?  Is it the pharmaceutical companies that closed most antibacterial drug discovery units or governmental rules (patents) that bias against antibacterial investments?  Of course, the answer is all of the above and more.  All I can offer is that we have to stop pretending that some magical antibiotic will be discovered. There will be no 10x20 to rescue our patients.  I would settle for 2x20 or how about "1 good one by 20".

As ID physicians, I think we need to stop pretending that we have effective antibiotics. We need to be more honest about the hopelessness of the situation. If a well-trained practicing oncologist isn't aware of the problem, we aren't doing our job. When we face facts, we will have a better chance of convincing the public and government to actually invest in infection prevention and antibacterial drug discovery. This isn't some Disney movie.

Been down so long...

being down don't bother me.  Having spent a few days here in Vancouver, I'm reminded of a paper published earlier this year out of British Columbia.  Gill et al, reported in CID results of a large 5422 person cohort of HIV+ patients with resistance testing during 1996-2008.  They described a drastic decrease in the incidence of new cases of HIV-1 drug resistance with the incidence rate of any newly detected resistance falling 12-fold from 1.73 cases per 100 person-months of therapy in 1997 to 0.13 cases per 100 person-months in 2008. I have posted Figure 1B below from the paper which shows declines in resistance to the major antiretroviral classes (PI, NRTI, NNRTI).

Another reason to like frogs

As if us toads needed another reason to like frogs, there is a new report out of the American Chemical Society meeting that suggests frog skin may be an excellent source for new antimicrobials including ones active against MRSA and acinetobacter. More than 100 potential compounds have been identified.  Now if we could just convince frog to let us sleep in more. That bit where he rips the calendar pages off until he gets to May is not that cool...

Article from BBC News

NPR's Science Friday on Antibiotic Resistance!!

On today's Science Friday Ira Flatow welcomed Dr. Stuart Levy from Tufts, Maryn McKenna the author of Superbug, Brad Spellberg from Harbor-UCLA and Elizabeth 'Betsy' McCaughey (Former Lt. Governor, New York and Death Panels - page 432). Stuart Levy is well known for his many years of work studying resistant organisms and developing new antimicrobials and Brad Spellberg is very well spoken. Brad's description of the debate around MRSA screening was fantastic and his explanation of the difficult issues surrounding new drug discovery (economic and FDA) was great. His call for actual research funding to figure out how to do terminal cleaning and figure out optimal prevention strategies was spot on.

Maryn McKenna, unfortunately, didn't get many words in but her comments around antibiotic stewardship in humans AND animals are very important. There is one point in the middle where Ira questions Ms. McCaughey's conflicts of interest around cleaning agents, listen for that. Near the end Ira brings up triclosan use in household products and Stuart Levy, having done much of the research on the harms associated with triclosan's use, offers a great description of why we should avoid it. Ira summarizing the discussion said that "we are going to devolve into the 18th century" where we won't have any effective antibiotics and "to me it sounds like you're just rearranging the chairs on the Titanic." Enjoy!

Direct audio link (here)
Website (here) with speaker info and audio link on the upper left side of the page