Antibiotics: There's no free lunch

A new, important paper in JAMA Internal Medicine from Sara Cosgrove's group at Johns Hopkins demonstrates the collateral damage of antibiotics. In this retrospective cohort study of 5,579 internal medicine inpatients, 1,488 (27%) received a parenteral or oral antibiotic for at least 24 hours. The most common indication for antibiotics was UTI, Adverse events due to antibiotics were captured over the 30-day period after antibiotic initiation, with the exception of C. difficile infection and MDRO infections, which were captured over the ensuing 90 days. Median duration of therapy was 7 days. Of the patients treated with antibiotics, 19% had no clinical indication for antibiotic therapy, and 20% developed at least one associated adverse event. The breakdown of adverse events is shown in the visual abstract below (note: for this analysis, I combined the 30- and 90-day outcomes). We are becoming more cognizant that antibiotics are not benign therapies. Kudos to Sara and her colleagues for their work in raising our awareness.

“The scandal isn't what's illegal, the scandal is what's legal”

This quote, attributed to Michael Kinsley, is applicable to a very disturbing trend that is having an increasing impact on antimicrobial availability: the acquisition of exclusive marketing rights (usually by small private firms) to inexpensive generic drugs in order to jack up their prices astronomically. The antimicrobials pyrimethamine, albendazole, cycloserine, flucytosine, and doxycycline have all experienced price increases of up to 5000%, and there have been several recent posts on the Emerging Infections Network about how this is limiting availability of these agents for those who desperately need them. 

I hope this NY Times story about the pyrimethamine saga draws more attention to this trend, and leads to some regulatory reforms to prevent this obvious price gouging. Because you-guessed-it, there is nothing illegal about this under U.S. law.

Fortunately, because it engenders bad press when people suffer and/or die due to unavailability of an essential drug, some of these “pharmaceutical companies”* will immediately send out the drug at a reduced price (or even without charge) if contacted by the treating physician. Such saints, these folks are….

*I put that term in quotes, because the company that owns marketing rights to pyrimethamine is founded and run by a hedge fund manager

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?

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/

Are you pro procalcitonin?

Clinicians over prescribe antibiotics. I spent several years exploring the risk-averse nature of physicians (specifically ID physicians) when it comes to avoiding treatment failure in diabetic foot ulcer, community-acquired pneumonia (CAP), and CVC bacteremia. Using binary choice contingent-valuation analysis our group determined that ID docs were very risk averse. For example, three of 34 ID physicians found a failure rate of 1% in CAP to be unacceptably high. So how do we acknowledge the risk-averse nature of clinicians, while at the same time safely improving antimicrobial stewardship through reducing over-prescription or shortening duration of therapy?

One possible and much heralded solution was going to be improved diagnostic microbiological tests, such as PNA FISH, which can rapidly detect clinically important (ie you need to alter therapy) pathogens, such as MRSA. These require waiting for positive blood cultures and haven't yet fully caught on, for whatever reason.  Importantly, these micro tests can't tell you if the patient is infected vs. colonized or what clinical syndrome they might have, such as pneumonia. Even a chest xray can't tell you if your patient has pneumonia.  That's why I was cautiously hopeful as I read a meta-analysis by Philipp Schuetz et al. of procalcitonin in directing antibiotic initiation and duration in acute respiratory infection, published online May 9th in CID.

Procalcitonin has gotten a lot of attention recently since it's been found that levels are high in severe bacterial infections but lower in viral or non-specific illnesses. Thus, algorithms that include procalcitonin cut-offs might help target initiation and withdrawal of antibiotic therapy without impacting clinical outcomes. To verify this claim, the authors reviewed 14 clinical trials with a total of 4221 patients to determine mortality, treatment failure and total antibiotic exposure in patients treated under procalcitonin-guided algorithms versus standard therapy. Mortality was similar in both groups (OR 0.94, 95% CI [0.71-1.23]) and treatment failure was slightly lower with procalcitonin (OR 0.82 [0.71-0.97]. Both of these were despite relatively poor-adherence in some of the studies. Importantly, total antibiotic exposure was decreased when using procalcitonin containing algorithms with a statistically significant reduction of 3.47 days. However, sample size was low when limited to ICU patients, so further studies are needed there.

These results do suggest that procalcitonin-containing antibiotic treatment algorithms may have an important role in respiratory tract infection therapy, particularly from a public-health, antibiotic resistance standpoint.  It remains to be seen if algorithms with limited clinical benefit for the individual patient but large potential benefits in terms of stewardship and public health will ever be widely adopted. Physicians are still risk averse, after all. Fingers crossed.

Source: Schuetz P. et al Clin Infect Dis 2012 (online May 9, 2012)

Image source: July 2009, Clinical Laboratory News

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

Hospital epidemiologists are killing pharma

Photo: 2old2play. com

A new report shows that the hospital acquired bacterial infections market for the time period 2010 through 2017 is expected to decline by a negative CAGR of 3.4% (click here if, like me, you need help understanding a CAGR). One of the major reasons cited for this decline in the market for these antibacterial drugs is a reduction in healthcare associated infections.

If you are interested in learning more about what's in this report, click here and submit your credit card information. For only $3,500 (about the same price as a course of fidaxomicin), the report can be yours.  

Deus ex machina (Part 4): Flavonoid-like Molecules

Flavo-Noid?

When I started the Deus ex machina "meme" three weeks ago, I had no idea that so many potential novel antimicrobials would just suddenly appear.  First we had tiny magnets, then we had DNA or RNA gold nanoparticles and now word comes that there is a newly synthesized family of flavonoid-like molecules with antibacterial and antifungal activity.

Fowler et al. in PLoS ONE examined flavonoids, which are abundant plant metabolites with anti-infective activity. They used a natural flavonoid scaffold to create novel flavanones and tested their efficacy versus E coli, B subtilis, Cryptococcus neoformans and Aspergillus fumigatus. They screened eight molecules and found that 4-chloro-flavanone was the most potent antimicrobial compound.  What did Ralph Waldo Emerson say? I think it's that "We judge of man's wisdom by his hope."  Keep hope alive.

Source: Fowler et al. PLoS ONE 2011

Via:  Hampton T, JAMA 2011