Archive for March 2015
By: Aminul Islam, Ph.D
Thanks to the serendipitous discovery of antimicrobial agents by the Scottish scientist, Sir Alexander Fleming in 1928, society at large has benefited tremendously from improved public health and advanced medical and agricultural practices. However, according to CDC (Centers for Disease Control and Prevention) reports, nearly two million people have become infected with bacteria that are resistant to antibiotics and at least 23,000 people each year die as a direct result of these infections in the U.S. This is in stark contrast to the statement supposedly made by the U.S. Surgeon General Dr. William Stewart in the 1960s that: ‘It was time to close the book on infectious diseases, and declare the war against pestilence won’. So is the golden age of antibiotics really coming to an end?
There are many issues which are thought to have contributed to the rise in antimicrobial resistance to antibiotics. They range from inappropriate prescribing by primary care physicians to reckless overuse within the agricultural industries. One major issue has been the inability of the pharmaceutical industry to continue producing new antibiotics to replace old ineffective ones. Indeed, the pipeline for developing new antibiotics has been pretty bare since 1987 as no new class of antibiotics for treating systemic infections has been developed. As a result, the marketing of a new antibiotic has become rather rare recently with a majority of the major pharmaceutical companies either closing their facilities or withdrawing from the pursuit of new antibiotic development; since it is deemed to be an unprofitable business venture. What is clear is that financial incentives are necessary to encourage research and development for novel antibiotics from within the pharmaceutical industry.
So how can we incentivize “Big Pharma” to once again see the development of new antibiotics as a profitable investment? In my opinion, this would require innovative public-private-partnerships and government policies which incentivize the development of new antibiotics without jeopardizing the preservation of current and future antibiotics. In particular, policies are needed which promote long-term antibiotic stewardship as well as sustainable business models for the private sector. This would be a tough balancing act considering that the success of nearly all pharmaceutical products are intrinsically linked to the number of units sold during the period of market exclusivity by employing aggressive marketing strategies to drive and increase sales – a practice which is all too common within the industry, but counterintuitive with regards to antibiotic preservation. Within the last year, six new antibiotics (dalbavancin, oritavancin, tedizolid, ceftobiprole, ceftazidime-avibactam and ceftolozane-tazobactam) have been approved under the FDA’s Qualified Infectious Disease Product (QIDP) framework based on the Generating Antibiotic Incentives Now (GAIN) Act, passed in July 2012, which gives these drugs an extra five years of market exclusivity. But this legislation does not either account for or guarantee long term antibiotic stewardship for these or any other antibiotics and in my opinion is not a comprehensive answer to the issue of antibiotic resistance.
I personally do not believe the golden age of antibiotics is at an end, primarily due to the attention this important issue is receiving lately (e.g. federal budget proposal for FY16) and by the governments response in setting up the President’s Council of Advisors on Science and Technology (PCAST) and executive order to combat antibiotic resistant bacteria. However, until we truly link both the incentives to developing antibiotics and the remuneration for using antibiotics directly to the conservation of current and future antibiotics, the threat of antibiotic resistance will not be fully eliminated and the market sector will remain disinterested to the needs of society for sustainable antibiotic stewardship.
By: Sylvina Raver, Ph.D.
The biomedical research enterprise in the United States is in trouble. Recent unprecedented volatility in federal research funding has prompted the biomedical workforce to grow at a faster pace than the number of available research positions. Funding booms, such as those that occurred in the late 1990’s and early 2000’s, enabled research institutions to train more young scientists, while simultaneously increasing the dependence of the entire research structure upon external federal funding. Subsequent funding cuts, as have occurred since 2003, cause the research system to contract and force young investigators into a saturated employment market after they complete their training. This workforce imbalance is a key driver of the hyper-competitive environment that now permeates the entire biomedical research endeavor and has prompted scientific leaders and professional societies, such as the Federation of American Societies for Experimental Biology (FASEB), to call the current state of US research “unsustainable,” and demand “immediate attention and action” to address its flaws.
Postdoctoral researchers, or postdocs, are vital to the research enterprise, as they perform much of the nation’s research, train junior scientists, and write grant applications and publications. Postdoctoral training conforms to an apprenticeship model in which postdocs are trained in the image of their mentor (the PI) and are expected to devote all of their effort toward conducting lab research. However, recent accounts suggest that only 15% of postdocs will go on to head a research lab. PI’s often lack knowledge about career trajectories outside of academia, and many universities and research institutions do not offer professional development for careers other than in research. The length of postdoctoral appointments has steadily increased, indicating that postdocs are struggling to find suitable positions after completing their training. Indeed, the average age at which a new investigator in the United States lands a tenure-track academic position is now 37 years old.
Despite the crucial role that postdocs play in the research community, they have long been considered an “invisible university”, as data on their numbers and career outcomes have not been well-documented. Around 30,800 to 63,400 postdocs are estimated to be currently pursuing science, health, or engineering research in the US. However, these estimates are grossly inaccurate, as these numbers do not include postdocs employed outside of academia, those training in the humanities, or postdocs with doctorates from non-US universities who may represent as much as 60% of the population. Postdocs often exist in a nebulous realm between employment categories and can thus find themselves without many benefits, such as health insurance or retirement contributions, afforded to other employees with comparable credentials and experience.
The National Postdoctoral Association’s (NPA) 2014 Institutional Policy Report revealed a typical postdoc in the US today is a scientist in their early to mid 30’s: who is likely a foreign citizen with a temporary visa, who holds their appointment for 5-6 years, is paid the minimum NIH National Research Service Award (NRSA) recommended stipend of $42,000, and who may be offered professional development only for a research career. Given the likelihood that postdocs will find a career away from the bench, training in skills relevant to an expanded sphere of employment is crucial.
The NPA is dedicated to improving the postdoc experience through education, advocacy, and community building. It convenes an annual meeting to pursue this mission in coordination with individual postdocs, Postdoctoral Associations (PDAs), Postdoctoral Offices (PDOs) and other organizations that share a stake in postdoctoral training. The 2015 meeting was held from March 13-15, during which attendees discussed pressing issues affecting the postdoc community and the biomedical research enterprise, and identified possible solutions to many of these challenges. While PDAs and PDO’s strive to enact the NPA’s recommendations at their home institutions, the NPA is actively consulting with national agencies, including the NIH, the National Science Foundation (NSF), and the National Academy of Sciences, on policy decisions that affect the entire postdoc community. Ongoing NPA advocacy efforts include proposed “increases for NIH training stipends, requirement for mentoring plans on NIH grants, more independent funding for postdocs, and increased data collection on postdocs, including tracking outcomes” (page 4 of the NPA’s 2014 Institutional Policy Report).
The NPA is not alone in its efforts, and through coordination with other groups, significant progress for postdocs has been made. A follow-up to a 2000 National Academies’ report titled, The Postdoctoral Experience Revisited, notes many major achievements. For example, the NPA’s creation in 2003 has provided a unified voice for the postdoc community, and more research institutions are participating in the NPA’s National Postdoc Appreciation Week, which recognizes postdocs’ efforts. Many universities are creating designated offices to better serve postdocs’ needs. The NSF now requires research proposals that include plans for hiring a postdoc to also include plans for mentorship. The American Association for the Advancement of Science (AAAS) has developed myIDP, an online tool that helps postdocs better understand available career options and helps them create individual development plans to better inform career decisions.
Despite these achievements, the 2014 National Academies report outlines six interconnected recommendations for improving postdoctoral training that will require concerted and coordinated efforts at all levels of the research enterprise for successful implementation:
- Period of Service: limit postdoc appointments to 5 years, barring extraordinary circumstances,
- Title and Role: reserve the title of “Postdoctoral Researcher” only for those requiring advanced research training,
- Career Development: expose graduate students to non-academic career paths in their first year of training, and explain that postdocs are only for those wishing to continue in research,
- Compensation and Benefits of Employment: raise the NIH NRSA postdoc starting salary to $50,000, annually adjust it for inflation, and provide the same benefits to postdocs that are provided to equivalent full-time employees,
- Mentoring: encourage host institutions and funding agencies to urge postdocs to seek advice from multiple mentors; hold institutions accountable for evaluating the quality of mentorship,
- Data Collection: maintain a database that tracks postdoctoral researchers, including non-academic and foreign-trained postdocs.
The venerated reputation of National Academy members lends credibility and political clout to these policy recommendations. However, some young investigators are eager to take more active roles in the future of the research enterprise. In October 2014, a team of Boston area postdocs held a symposium titled, “The Future of Research”. This event included workshops that elicited the opinions of postdoc and graduate student participants on “problems and solutions surrounding training, the structure of the research workforce, funding, and incentives and rewards in science.” A report of this event was quickly made available and distilled many ideas discussed during this symposium into three overarching recommendations:
- Increase connectivity between junior scientists and other stakeholders
- Increase transparency of career outcomes for postdocs and expectations for individual postdoctoral appointments
- Increase investment in junior scientists to allow for greater independence at this stage of training
The Future of Research organization provides resources for those interested in convening similar symposia to engage their local postdoc communities.
The challenges faced by the postdoctoral research community are complex and require coordination among all stakeholders to remedy. Although postdocs may feel as though they toil in the background of the research enterprise, it is encouraging to know that organizations such as the NPA, the National Academies, PDAs, PDOs, and grassroots assemblies of postdocs are working daily to enact meaningful change.
By: Ashley Parker, Ph.D
Antibiotics have been used to treat bacterial infections for more than 70 years. Bacteria and fungi naturally produce these antimicrobial compounds to kill other microbes in their environment. The first antibiotic, penicillin, was discovered by Alexander Fleming, a professor of bacteriology at St. Mary’s Hospital in London. Most people are familiar with this antibiotic, which has saved many lives since the 1940s. Unfortunately, what was once considered to be a “miracle drug” in treating infectious diseases is no longer effective against some bacterial strains. Many classes of antibiotics have been discovered since the discovery of penicillin but unfortunately, the widespread use and abuse of those antibiotics has led to increased selection for antibiotic resistant bacteria. Microbes use various mechanisms to prevent antibiotics from killing, and thus fail to respond to antibiotic treatments. Due to the rise of antibiotic resistant bacteria, it is important to understand current strategies and developments to combat antibiotic resistance, and the various challenges.
There have been several reports of “superbug” outbreaks in the United States and across the world. Tuberculosis outbreaks in Europe are a major concern, with increasing cases of multidrug resistant tuberculosis (MDR-TB). The World Health Organization (WHO) reported in the 2014 Antimicrobial Resistance Global Report on Surveillance that 3.6% of new TB cases and 20.2% of previously treated cases were estimated to be MDR-TB with higher incidences in Eastern Europe and central Asia. Within the report on antimicrobial resistance, the WHO also reported national data on the bacterial pathogens: E. coli, K. pneumonia, and S. aureus showing that the proportion of these bacteria resistant to commonly used antibiotics was more than 50% in various settings. Recent outbreaks in the U.S. involved two California hospitals and one in Hartford, Connecticut that were associated with carbapenem-resistant Enterobacteriaceae (CRE) and drug resistant E. coli respectively.
Over the past 40 years, no new classes of antibiotics have been developed to treat gram-negative bacilli, such as E. coli and those seen in recent outbreaks. The U.S. Food and Drug Administration (FDA) has only approved two systemic antibiotics for use in humans from 2008 to 2014. According to the Centers for Disease Control and Prevention (CDC), at least 2 million people become infected with drug resistant bacteria in the United States and 23,000 deaths are reported to be directly related to these infections. As of December 2014, the Pew Charitable Trusts, published that 37 new antibiotics were in development. Of the 37 antibiotics, 10 were in Phase I clinical trials, 18 in Phase II, 8 in Phase III, and only one had been submitted for a new drug application. Most of these antibiotics are reported to be potentially effective against the current drug resistant bacteria; however, not all of the antibiotics. Considering there is only a single drug that has passed phase 3; this is clearly a major public health concern, and combating antibiotic resistance in the future will likely require national and international efforts. The U.S. has begun efforts to deal with this multifaceted problem with Congress passing the Generating Antibiotic Incentives Now (GAIN) law as part of the FDA, to extend the time of generic competition by 5 years for antibiotics that are proven to effectively treat infectious diseases.
On September 18, 2014, President Obama signed an executive order to direct federal departments and agencies to combat the rise of antibiotic resistance. In addition, with sponsorship from the National Institutes of Health and the Biomedical Advanced Research and Development Authority, the Obama administration announced a $20 million prize to rapidly implement point-of-care diagnostic tools, to identify multidrug resistant infections in healthcare facilities. In this executive order, the Presidential Advisory Council on Combating Antibiotic-Resistant Bacteria was established to provide oversight for programs and policies that intend to preserve antibiotic effectiveness, along with many other efforts. To preserve the power of current antibiotics, the CDC is encouraging hospital CEOs and medical officers to appoint leaders to support program outcomes and improve prescribing practices, monitor prescribing and antibiotic resistance patterns, and offer education about antibiotic resistance to health care providers. The Departments of Health and Human Services, Defense, and Veteran Affairs will also serve a major role in improving antibiotic stewardship in compliance of the efforts outlined by the CDC.
Aside from the healthcare industry, the agricultural industry also plays a significant role in combating antibiotic resistance due to the use of antibiotics for farm animals — which may have led to reported outbreaks of antibiotic resistant strains in animal livestock. In 2007, the U.S. experienced the first reported outbreak of methicillin-resistant Staphylococcus aureus (MRSA) in farm pigs. MRSA infections can be life threatening and account for half of the more than 14 million skin and soft-tissue infections seen in the U.S each year. According to the CDC, there are approximately 100,000 cases of invasive infections each year. However, the White House has advised the U.S. FDA to continue making efforts to eliminate the use of antibiotics for the growth-promotion of animals in agricultural settings, but allow for medically important antibiotic usage that will be monitored by the National Healthcare Safety Network. In addition, the White House advisory council will provide insight and recommendations for strengthening the surveillance of antibiotic resistant infections, promote advanced research on new antibiotic treatments, seek antibiotic alternatives used for agricultural purposes, and improve global efforts to tackle antibiotic resistance.
On March 16, 2015, Gerard O’Dwyer published an article discussing a methicillin-resistant Staphylococcus aureus (MRSA) outbreak in Norway. The Norway food safety authority discovered six new pig herds infected with livestock-associated methicillin-resistant S. aureus, also known as LA-MRSA. International actions on combating antibiotic resistance, particularly for MRSA and C. difficile infections, are of political interest in England. In September 2013, the United Kingdom (UK) released its Five Year Antimicrobial Resistance Strategy, cosponsored with the Veterinary Medicines Directorate of the Department for Environment, Food and Rural Affairs, the Northern Ireland Executive, the Scottish government, the Welsh government, and the UK Public Health agencies. The antimicrobial resistance action plan covered seven core areas: addressing the efforts to improve infection prevention and control practices, optimizing prescribing practice, improving professional education, training, and public engagement; developing new drugs, treatments, and diagnostics; improving access and use of surveillance data; improving identification and prioritization of antimicrobial resistance; and strengthening international collaboration.
Overall, fighting antibiotic resistance is a major public health concern in the U.S. and abroad and must involve multiple entities, including the federal government and agencies, health care professionals, and individuals of the general public. The Obama administration and other international governments have prepared extensive guidelines and taken the necessary measures to effectively address the threat of antibiotic resistance; however the battle against antimicrobial resistance will be a continuing effort that is not expected to resolve immediately.