Delving Deeper: Living in the Post-Antibiotic Era

By Yong-Bee Lim

The Post-Antibiotic Era Problem: What are the Issues, and How Can Adaptive Clinical Trials Potentially Help?

Nostalgia is a powerful thing. When people get nostalgic, they are cognitively living in the past; in this constructed past, the past seems rosy, and often conceived of as more positive than the present. That said, even with rose-tinted glasses, it is hard to argue that life (if defined as survivability) was better before the introduction of antibiotics. For example, mortality rates from pneumococcal pneumonia were 30-35% in the pre-antibiotic era, with the therapy often being quarantining patients.[1] Antibiotics have allowed for both the morbidity and mortality rates of pneumococcal pneumonia to drop to nearly zero in developed countries.[2] Furthermore, antibiotics allow procedures that would have been impossible in a pre-antibiotic era; organ transplants, invasive procedures, and intensive care units would not be possible without effective antibiotics.

A recent piece of news to hit the public health radar involves a man in New Zealand named Henry Pool. Pool, while teaching English in Vietnam, was operated on following a brain hemorrhage. When flown following the operation to a Wellington hospital, it was discovered that he carried a bacteria strain identified as KPC-Oxa 48: a strain of bacteria that is resistant to every antibiotic currently available to man. To contain the possibility of the strain of bacteria getting out, Pool was forcibly quarantined for 6 months until he passed away. [3]

This recent death in New Zealand highlights a threat that looms ever closer in the public health horizon: the post-antibiotic era. Due to a number of factors, including over-prescription of antibiotics to patients and over-use of antibiotics in farming and animal cultivation, bacteria have undergone evolutionary pressures to resist and overcome the mechanisms of our current arsenal antibiotics; several adaptations include the production of enzymes to modify antibiotics, cell wall changes that prevent the ingress of antibiotics inside the bacterium, and the creation of pumps to transfer antibiotics outside of the cell before the antibiotic’s effects are actualized. Furthermore, evidence points to the fact that multiply-resistant bacteria are not staying confined to hospitals as they traditionally have; certain bacteria such as Streptococcus pneumonia and Staphylococcus aureus with partial/complete resistance to penicillin have been detected in community populations.[4]

The concept of antibiotic resistance is not a foreign one to scientists and individuals in the public health sector. Staphylococcus aureus was actually noted to have started developing antibiotic resistance to penicillin as early as the 1940s.[5] Despite this knowledge that antibiotic resistance could, and would, develop over time, very little is available in regards to innovative new antibiotics to counter the rising threat of antibiotic-resistant bacteria. There has been “no major classes of antibiotics introduced” between the years of 1962 and 2000;[6] furthermore, while representatives of novel antibacterial classes (linezolid: 2000, daptomycin: 2003, retapamulin: 2007) have been registered, the chemical classes from whence these representatives originate were patented or reported historically (oxazolidnones: 1978, acid lipopetides: 1987, pleuromutilins: 1952).[7]

If the threat is realized, then, why is there such paucity in the development and production of novel and effective antibacterial therapies? Part of the equation has to do with the society we live in; money is important to companies.  Over the past several decades, a number of large pharmaceutical companies have drastically cut funding and maintaining the internal capacity for R&D of antibacterial therapies. It is often argued that this decline is partially explained by the fact that pharmaceutical companies seek to shift R&D resources from antibacterial drug discovery programs to other, more profitable therapy areas such as musculoskeletal and central nervous system (CNS) drugs.[8],[9] The net effect of various economic barriers involved in the development of an antibiotic (if successful) is a net loss of $50 million dollars compared to a $1 billion gain for a new musculoskeletal drug at the time of discovery.[10] In addition, mergers and take-overs of pharmaceutical companies often result in a restructuring of priorities and personnel; these restructures have often included the loss of research groups with expertise in antibiotic drug discovery.[11]

So if part of the issue is economics, what can be done to better galvanize and incentivize pharmaceutical companies to come back and do R&D on antibacterial drugs? One area where companies often hemorrhage money is in the clinical trials necessary to prove both the safety and efficacy of a product. Oftentimes, the bulk of R&D funds are spent on clinical trials. Clinical trials (depending on the size of the sample needed to test the product, the cost of developing the product itself, and other factors) can run in the ballpark of $100 million dollars per trial; with a minimum of 3 phases of clinical trials (with a high probability of repeating at least one phase of a trial), it is easy to see a successful product would cost a minimum of $400 million dollars in clinical trials alone.[12]

Under the current model of clinical trials, trials are clearly demarcated between phases (Clinical Phase 1, Clinical Phase 2, and Clinical Phase 3) that must be done in a sequential fashion. Furthermore, these trials are rigid in the fact that parameters may not be changed during the course of a trial; all participants must be kept throughout the trial, dosages may not be altered, and trials (except under certain circumstances) must be completed until the end. Among a number of situations, this lock-step approach inflates costs when observations might indicate:

–          A certain subset is not responding to a dose (perhaps the dose is too low)

–          The entire sample is not responding to the product (at any dose)

Using innovative, high-level Bayesian biostatistics, a new avenue of clinical research design is being explored that may help alleviate some of the costs of clinical trials. Adaptive clinical trials are specifically designed studies that are meant to “adapt” as a clinical trial proceeds; these adaptations occur through an analysis of the accumulated results in a trial.[13] As opposed to the lock-step and rigid clinical trial structure that is currently used, adaptive clinical trials allow modifications to be introduced during the trial phase. These modifications could include, but are not limited to:

–          Sample size re-estimation: If the number of people for a trial is too small or too large, this can be adapted during the trial.

–          Early stopping of clinical trials: In the event that there is evidence that the product isn’t performing the way it is supposed to (lack of efficacy), trials can be shut down to save funds and resources.

–          Dropping suboptimal groups: In the event that there is evidence that the product isn’t effective in a subgroup of the trial sample (perhaps a group with a low dose is not presenting results), then the group could be dropped to save funds and resources.

–          Overlapping trials: Adaptive trials could overlap phases (the tail end of phase 1, for example, could overlap the beginning of phase 2), resulting in faster clinical trial completion and, hopefully, swifter licensure.

It should be noted that this type of approach is very new, and is only just garnering use in various areas that require clinical trials. For example, it has not been used, as of this post, for the development of Medical Countermeasures (MCMs). However, if it can be successfully executed, it holds possibilities in significantly cutting down both the temporal constraints, as well as the financial burdens, of attaining the novel and effective antibiotics that are necessary to help curb the growing antibiotic-resistant bacteria threat.

Perhaps the phraseology “post-antibiotic era” is too strong; it seems to evoke a sense of fear, and fails to address the idea that future innovations exist in the pipeline to potentially deal with issues of current levels of antibiotic resistance. However, what can be said is that we are starting to run out of options in our bag of tricks, and it will take more than a wave of a wand and an “abracadabra” to resolve this threat to the status quo: a public health era in which antibiotics work against bacteria to increase survivability. While there are multi-faceted issues contributing to this issue, the ability to help make antibacterial R&D more financially viable for pharmaceutical companies (through the use of innovations such as adaptive clinical trials) could help in dealing with this public health concern.
______________________________

Yong-Bee Lim is a PhD student in Biodefense at George Mason University. He holds a B.S. in Psychology and an M.S. in Biodefense from George Mason University as well. Contact him at ylim3@masonlive.gmu.edu or on Twitter @yblim3.


[1] Shai Ashkenazi. (2012). “Beginning and possibly the end of the antibiotic era,” Journal of Pediatrics and Child Health, 49 (3): pp. 179 – 182.

[2] RP Wenzel and MB Edmond. (2000). “Managing antibiotic resistance,” New England Journal of Medicine, 343: pp. 1961 – 1963

[3] “Kiwi dies with bug no drug could beat,” New Zealand Herald, accessed 11/23/2013: http://m.nzherald.co.nz/nz/news/article.cfm?c_id=1&objectid=11159413

[4] LF Chen, T Chopra, and KS Kaye. (2009). “Pathogens resistant to antimicrobial agents,” Infectious Disease Clinics of North America, 23: pp. 817 – 845

[5] “Methicillin-Resistant Staphylococcus aureus (MRSA),” National Institute of Allergy and Infectious Diseases, accessed 11/26/2013, http://www.niaid.nih.gov/topics/antimicrobialresistance/examples/mrsa/pages/history.aspx

[6] MA Fischbach and CT Walsh. (2009). “Antibiotics for emerging pathogens,” Science, 325: pp. 1089 – 1093

[7] Lynn L. Silver. (2011). “Challenges of antibacterial discovery,” Clinical Microbiology Reviews, 24 (1): pp.71 – 109

[8] S. Projan. (2003). “Why is big pharma getting out of antibacterial drug discovery?” Current Opinion in Microbiology, 6 (5): pp. 427 – 430

[9] R Finch and P Hunger. (2006). “Antibiotic resistance – action to promote new technologies,” Journal of Antimicrobial Chemotherapy, 58 (Suppl): pp. 3 – 22

[10] Priya Sharma and Adrian Towse. (2011). “New drugs to tackle antimicrobial resistance: Analysis of EU policy options.”

[11] I. Chopra. (2008). “Treatment of health-care-associated infections caused by Gram-negative bacteria: a consensus statement,” Lancet Infectious Diseases, 8: pp. 133 – 139

[12] “How the FDA Stifles New Cures, Part I: The Rising Cost of Clinical Trials,” Forbes, accessed 11/26/2013, http://www.forbes.com/sites/aroy/2012/04/24/how-the-fda-stifles-new-cures-part-i-the-rising-cost-of-clinical-trials/

[13] Donald A. Berry. (2010). “Adapative clinical trials: The promise and the caution,” American Society of Clinical Oncology, 29 (6): pp. 606 – 609

The Pandora Report 10.18.13

Highlights include a MERS-free hajj?, Craig Venter and bioterrorism, coronaviruses in hedgehogs,  DoD contributing to key biodefense infrastructure, bacteriophages eating superbugs, and (briefly) the Ebola cure and the oh-so-secret botulinum toxin. Happy Friday!

Hajj Numbers Down In 2013 By 1 Million Over MERS Virus Fears

Public health officials globally have kept a nervous eye on Saudi Arabia over the last week, as hajj brought 1.5 million pilgrims into Mecca, and potentially into contact with MERS. However hajj is concluding, and so far, not  a single case of MERS has emerged from the Muslim holy city. While it’s too early to tell with certainty whether this year’s hajj has been totally MERS-free, credit where credit is due.  Saudi Arabia was careful to institute a slew of preventative measures designed to prevent the virus’ spread, including severely limiting visas to susceptible populations, mandating mask-wearing in high density spaces, and a broad information campaign emphasizing good hygiene. We’re impressed (and grateful!).

International Business Times – “Hajj placed 1.75 million foreign pilgrims in contact with 1.4 million Saudi pilgrims last year, and officials feared that such contact could prove a deadly mix for a disease that has been, thus far, largely contained within the kingdom. Interior Minister Prince Mohammed bin Nayef said international numbers were down 21 percent to 1.37 million pilgrims from 188 countries this year, while the number of pilgrims from within the kingdom is believed to be half of what it was last year…Saudi Minister of Health, Abdullah bin Abdulaziz Al-Rabeeah, announced late Saturday that all health facilities were ready for hajj pilgrims, with some 22,000 health workers (3,000 more than previous years) on standby to help the ill or injured. He added that there had been no epidemic or coronavirus cases among pilgrims thus far.”

Craig Venter (briefly) Discusses Bioterrorism 

If you’re even tangentially involved in the biosciences, you already know that Craig Venter was the lead scientists of the Human Genome Project, which was the first to successfully characterize an entire human genome. It took Venter and his team thirteen years and nearly three billion dollars to sequence his genome. Today, it’s possible to sequence a human genome in less than a month at under $5,000, leading many scientists to worry about the potential of terrorists simply sequencing highly pathogenic bugs. Popular Mechanics caught up with Venter in advance of his new book, Life at the Speed of Light: From the Double Helix to the Dawn of Digital Life, and asked him about, amongst other things, synthetic biology and biological terrorism.

Popular Mechanics – [Venter, on his biggest concern for synthetic biology] “Certainly the biggest concern is the potential for bioterrorism. But using synthetics for bioterrorism is a huge, huge, huge, challenge. Right now there are so many sources of materials for bioterrorism that it’s unlikely that somebody would go to all the difficulty to synthetically make it. For example, anthrax exists on most cattle farms. Any dead cow has a good chance of having anthrax in it, so it’s not like you need to get anthrax from some high security lab. But certainly, in theory, people could make things like smallpox that aren’t readily available. My main concern is people doing biology in their kitchens. It’s great that so many people are curious about biology, but without proper training these DIY biologists don’t learn the right safety approaches and mechanisms. Someone could inadvertently cause harm to a lot of people. Like any new frontier with powerful technology, people have to think about it carefully. What are its implications? How can we regulate it without over-regulating it?”

Bacteria-eating viruses ‘magic bullets in the war on superbugs’

Researchers at the University of Leicester have isolated a new strain of bacteriophage – viruses which infect and kill bacteria – which specifically targets the bacteria Clostridium difficile. The use of phages instead of comparatively indiscriminate antibiotics in treatment would help diminish the over-prescription antibiotics, reduce the likelihood of antibiotic resistance, and preserve healthy host bacteria. One of the researchers raises a very good point – with fewer and fewer new antibiotics discovered, and more and more cases of antibiotic resistance, an earnest search for viable alternatives is necessary.

University of Leicester – “Dr. Clokie and her team have achieved the remarkable feat of isolating and characterising the largest known set of distinct C. diff phages that infect clinically relevant strains of C. diff. Of these, a specific mixture of phages have been proved, through extensive laboratory testing, to be effective against 90% of the most clinically relevant C. diff strains currently seen in the U.K. As a testament to their therapeutic potential, these phages, that are the subject of a patent application, have been licensed by AmpliPhi Biosciences Corporation – a US-based biopharmaceutical company and pioneers in developing phage-based therapeutics. AmpliPhi have already made progress in developing phages targeted against Pseudomonas aeruginosa, a pathogen that causes acute, life-threatening lung infections in cystic fibrosis patients. They were also the first biopharmaceutical company to demonstrate the effectiveness of Pseudomonas phages in controlled and regulated human clinical trials.”

DOD Funding Contributes to U.S. Biodefense Infrastructure

The Department of Defense has co-funded the Texas A&M Center for Innovation in Advanced Development and Manufacturing, which was created in response to the 2009 influenza pandemic. The Center’s primary focus is flexible and fast development of therapeutics in response to novel disease outbreaks. Its primary investigator, Dr. Brett P. Giroir, formerly of DARPA, describing the need for the Center explained that “[l]iterally, what once took weeks during medical school to produce in a multimillion-dollar laboratory can be done [today] in an afternoon on a benchtop by someone with a relatively less degree of scientific training…So the barriers to entry have decreased’. We couldn’t agree more.

DoD – “The facility is called the National Center for Therapeutics, or NCTM, and a key feature there is the use of modular and mobile stand-alone biopharmaceutical clean rooms, called modular clear rooms, or MCRs. The initial MCR concept was funded by DOD through DARPA and the Army Research Office, Giroir said. NCTM is the core facility and main site for developing and manufacturing medical countermeasures and vaccines against chemical, biological, radiological and nuclear threats for the Texas A&M Center for Innovation, he added. Another part of the Center for Innovation’s biomanufacturing infrastructure is the Caliber Biotherapeutics Facility, Giroir said. Caliber was developed and built through Texas A&M and G-CON Manufacturing, with funding from the DARPA Blue Angel Program. According to a 2012 DARPA news release, the Blue Angel Program demonstrated a flexible and agile capability for DOD to rapidly react to and neutralize any natural or intentional pandemic disease.”

Characterization of a novel betacoronavirus related to MERS-CoV in European hedgehogs

It’s understood that bats are the established hosts for viruses similar to human coronaviruses, which prompted researchers to wonder if hedgehogs, which are closely related to bats, carry similar viruses. Researchers at the  University of Bonn in Germany acted on this hunch, and discovered a  novel “sister” betacoronavirus species in European hedgehogs. We’re disappointed – staying away from bats is fine because we don’t want rabies and bats are odd-looking, but hedgehogs? Really?

Journal of Virology – “58.9% of hedgehog fecal specimens were positive for the novel CoV (EriCoV) at 7.9 Log10 mean RNA copies per ml. EriCoV RNA concentrations were higher in the intestine than in other solid organs, blood and urine. Detailed analyses of the full hedgehog intestine showed highest EriCoV concentrations in lower gastrointestinal tract specimens, compatible with viral replication in the lower intestine and fecal-oral transmission. 13 of 27 (48.2%) hedgehog sera contained non- neutralising antibodies against MERS-CoV. The animal origins of this betacoronavirus clade including MERS-CoV may thus include both bat and non-bat hosts.”

In Case You Missed It:

Working on Ebola: We are very supportive of any treatment which helps mitigate our very real fear of Ebola. 
– Scientists Withhold Details of New Botulinum Toxin: We get it. We even agree. We’re curious if you do too.

(image credit: Michael Gäbler)