Antibiotic Resistance

“The discovery of antibiotics in the 1930s fundamentally transformed the way physicians care for patients, shifting their approach from a focus on diagnoses without means to intervene into a treatment-focused approach that saves lives. Now, nearly 70 years later, we’ve reached a critical point in treating infectious diseases: new drugs are not being developed at anywhere near the pace necessary to keep ahead of the natural ability of bacteria to evolve and defend themselves against antibiotics. The result is that some of our most powerful drugs are becoming useless…. New antibiotic development has slowed to a standstill due to market failure and regulatory disincentives. Antibiotics aren’t as profitable as other drugs (e.g., drugs to treat diabetes or asthma, which patients take for years). Also, the US Food and Drug Administration has long delayed publishing workable guidances describing how companies should design antibiotic clinical trials. Moreover, once a new antibiotic makes it to market, physicians hold it in reserve for only the worst cases rather than rushing to use it on all their patients due to fear of drug resistance. These economic and regulatory disincentives have made it far too difficult for companies to continue developing new antibiotics.” Infectious Diseases Society of America, “Antibiotic Resistance”.

“For approximately the first 60 years of the “Antibiotic era”, which effectively began 75 years ago with the introduction of clinical antibiotics, drug innovation had outpaced the development of antimicrobial resistance. More recently, the spread of drug resistance has outpaced the development of new drugs… Drug resistance, especially pan-drug resistance, is an issue that was previously a major consideration only in a hospital setting but is increasingly becoming a community-level concern as well; its existence outside of a clinical setting has made it more unpredictable and harder to control. Although the number of individuals infected with multi-drug resistant infections in the United States is relatively small—depending on one’s definition it is estimated in the thousands—there may be the potential for rapid spread…. The public health impact of antimicrobial resistance is a reality today. Within the year CDC is expected to publish a report with estimates of the number of serious infections caused by the most important antimicrobial resistant pathogens.” Notes from a conversation with Steve Solomon and Jean Patel of the Centers for Disease Control and Prevention, 6/18/2013.

2.

“More recently, the spread of drug resistance has outpaced the development of new drugs for two primary reasons: 1)Most of the “easy to identify” antibiotic agents have already been developed. It is becoming increasingly difficult from a scientific point of view to develop new drugs for the same diseases. 2)The economic incentives that face the pharmaceutical industry do not favor the development of new antibiotics. It is not considered profitable to invest in research and development of new antibiotics.” Notes from a conversation with Steve Solomon and Jean Patel of the Centers for Disease Control and Prevention, 6/18/2013.

“New antibiotic development has slowed to a standstill due to market failure and regulatory disincentives. Antibiotics aren’t as profitable as other drugs (e.g., drugs to treat diabetes or asthma, which patients take for years). Also, the US Food and Drug Administration has long delayed publishing workable guidances describing how companies should design antibiotic clinical trials. Moreover, once a new antibiotic makes it to market, physicians hold it in reserve for only the worst cases rather than rushing to use it on all their patients due to fear of drug resistance. These economic and regulatory disincentives have made it far too difficult for companies to continue developing new antibiotics.” Infectious Diseases Society of America, “Antibiotic Resistance”.

3.

“If current trends continue unabated, the future is easy to predict. Some experts say we are moving back to the pre-antibiotic era. No. This will be a post-antibiotic era. In terms of new replacement antibiotics, the pipeline is virtually dry, especially for gram-negative bacteria. The cupboard is nearly bare. Prospects for turning this situation around look dim. The pharmaceutical industry lacks incentives to bring new antimicrobials to market for many reasons, some of which fall on the shoulders of the medical and public health professions. Namely, our inability to combat the gross misuse of these medicines. From an industry perspective, why invest considerable sums of money to develop a new antimicrobial when irrational use will accelerate its ineffectiveness before the R&D investment can be recouped? A post-antibiotic era means, in effect, an end to modern medicine as we know it. Things as common as strep throat or a child’s scratched knee could once again kill.” Speech by Dr. Margaret Chan, Director-General of the World Health Organization, 03/14/2012.

“In the meantime, microbes continue to become more resistant, the antibiotic pipeline continues to diminish, and the majority of the public remains unaware of this critical situation. The result of insufficient federal funding; insufficient surveillance, prevention, and control; insufficient research and development activities; misguided regulation of antibiotics in agriculture and, in particular, for food animals; and insufficient overall coordination of US (and international) efforts could mean a literal return to the preantibiotic era for many types of infections.” Spellberg et al. 2008.

“It is difficult to accurately convey the enormous impact effective antibiotics have had in saving patients’ lives and eliminating tremendous suffering in the US and throughout the world. The most fundamental impact of the introduction of antibiotics was a dramatic decline in death from bacterial infections of all types. For example, the overall mortality rate from infectious diseases in the US fell by ∼220 per 100,000 population (75%) over the first 15 years of the antibiotic era [106]. Almost overnight, mortality rates for diseases such as pneumonia, endocarditis, and meningitis dropped substantially after the introduction of new antibiotics (Table 3). Indeed, so enormous were the mortality benefits of antibiotics that all subsequent medical advances since the early 1950s—including the advent of critical care medicine—have resulted in only minor further reductions in death from infections. Specifically, during the second half of the 20th century, despite all intervening advances in medical care, mortality rates from infections declined only by an additional 20 per 100,000, less than 10% of the decline achieved immediately following the availability of antibiotics [106]. The US federal government recognized this plateau effect in reduction of mortality from infections through the 1950s and 1960s, and understood [107] that it was due to the remarkable power of antibiotics [108–109]. Beyond saving lives of infected patients, today the enormous efficacy of antibiotics enables conduct of complicated and deeply invasive surgery, aggressive chemotherapy for treatment of cancer, fundamental elements of critical care such as central venous catheter placement and mechanical ventilation, supportive care for premature infants, and solid and liquid organ transplantation. None of these medical advances would be feasible without effective antibiotics to prevent and treat the infections that occur as a side effect of the advances themselves. Indeed, one of the leading physicians of the 20th century, Dr. Walsh McDermott, a Lasker Award winner who served as first president of the Medical Board of the National Academy of Sciences (precursor to the Institute of Medicine), commented that: ‘It is not too much to state that the introduction of [antibiotics] has represented a force for change in the 20th century of the same general kind as James Watt’s modification of the steam engine did in the 18th.’ [110] In short, as described by both Dr. McDermott and Dr. Lewis Thomas [111], the power of antibiotic therapy resulted in nothing less than a total revolution in the practice of medicine. Antibiotics fundamentally transformed the profession from a diagnostic, non-interventional field to a therapeutic, interventional profession. The loss of effective antibiotic therapy due to antimicrobial resistance and the withering antibiotic R&D pipeline will result in a great increase in deaths from infections. This issue—the availability of effective antibiotics—is not a ‘lifestyle’ issue, and the loss of such agents is not theoretical. We are facing a worldwide health crisis that already is resulting in deaths and maiming of patients, and will increasingly do so in the coming decades unless urgent action is taken. The time for debating the problem has passed. Immediate action is critically needed, as outlined in this policy paper.” Infectious Diseases Society of America 2011.

4.

“It is difficult to accurately convey the enormous impact effective antibiotics have had in saving patients’ lives and eliminating tremendous suffering in the US and throughout the world. The most fundamental impact of the introduction of antibiotics was a dramatic decline in death from bacterial infections of all types. For example, the overall mortality rate from infectious diseases in the US fell by ∼220 per 100,000 population (75%) over the first 15 years of the antibiotic era [106]. Almost overnight, mortality rates for diseases such as pneumonia, endocarditis, and meningitis dropped substantially after the introduction of new antibiotics (Table 3). Indeed, so enormous were the mortality benefits of antibiotics that all subsequent medical advances since the early 1950s—including the advent of critical care medicine—have resulted in only minor further reductions in death from infections. Specifically, during the second half of the 20th century, despite all intervening advances in medical care, mortality rates from infections declined only by an additional 20 per 100,000, less than 10% of the decline achieved immediately following the availability of antibiotics [106]. The US federal government recognized this plateau effect in reduction of mortality from infections through the 1950s and 1960s, and understood [107] that it was due to the remarkable power of antibiotics [108–109].” Infectious Diseases Society of America 2011.

However, the data from reference 106 in the quote above reflects the fact that roughly 75% of the reduction in infectious disease mortality in the U.S. over the course of the 20th century came before the widespread deployment of antibiotics. Centers for Disease Control and Prevention 1999: 

In addition, the subsequent widespread deployment of vaccines accounts for some of the reduction in mortality since the deployment of antibiotics, and may substitute for them to some extent: “Although not a solution in the short-term, vaccines could be highly impactful interventions. For instance, the introduction of a vaccine for the bacteria causing pneumococcal pneumonia has helped reduce the incidence of AR in those infections.” Notes from a conversation with Steve Solomon and Jean Patel of the Centers for Disease Control and Prevention, 6/18/2013.

5.

“The problem of antimicrobial resistance is not specific to bacteria—medically important viruses (e.g., HIV, influenza), fungi (e.g.,Candida,Aspergillus), and parasites (e.g., malaria) also develop antimicrobial resistance. However, a unique convergence of overuse and misuse of antibiotics, the remarkable genetic plasticity of bacteria, the acquisition of resistant bacterial infections in both community and hospital settings, and a market failure of antibiotic development has created an enormous public health concern regarding antibiotic resistance in bacteria. For this reason, antibiotic resistance is the primary focus of this policy paper. Paradoxically, concomitant with the rise of antibiotic-resistant bacteria, US Food and Drug Administration (FDA) approval of critically needed new antibiotics has dramatically slowed (Figure 1) [9–12]. Of great significance, nearly all major pharmaceutical companies have withdrawn from or greatly downsized their antibiotic research and development (R&D) programs over the past two decades, and the egress from the market is actively continuing. The combined threat of increasing numbers of drug-resistant bacteria and the diminishing antibiotic pipeline places us at risk not only from health care-associated and community-acquired infections, but from threats (bioterrorism, pandemics) that could affect our nation’s security. To reverse this trajectory and call policymakers’ attention to the growing crisis, IDSA launched its Bad Bugs, No Drugs advocacy campaign in 2004 [49]. Unfortunately, antibiotic resistance and the waning approvals of new antibiotics have only worsened since 2004. Since then, IDSA has undertaken many clinical, scientific and public policy activities, including: 1) published practice guidelines on the development of antimicrobial stewardship programs for hospitals [50] and on the prevention and management of C. difficile infections [51], along with the Society for Healthcare Epidemiology of America; 2) co-sponsored, along with FDA’s Center for Drug Evaluation and Research (CDER), workshops on the development of new antibiotics for Community-Acquired Bacterial Pneumonia (CABP) [52,53] and Hospital-Acquired Bacterial Pneumonia/Ventilator-Associated Bacterial Pneumonia (HABP/VABP) [54]; 3) published data in support of new antibiotic development for skin and soft tissue infections [55]; 4) co-sponsored, along with FDA’s Center for Devices and Radiological Health (CDRH), a workshop on diagnostics for respiratory infections; 5) proposed new research protocols on optimizing antibiotic effectiveness and antimicrobial stewardship for federal support; 6) testified at FDA Anti-Infective Drug Advisory Committee meetings and other FDA hearings and at Congressional briefings and hearings; 7) supported the Institute of Medicine Forum on Microbial Threats’ 2010 Workshop on Antimicrobial Resistance [56]; and 8) assisted members of Congress in drafting legislation introduced in the 110th and 111th sessions of Congress designed to directly address antimicrobial resistance issues [9]. In 2010, in recognition of the need for creative, new ideas to address the antibiotic pipeline problem and a measurable goal by which to gauge progress, IDSA launched the “10 × ’20 initiative” [57]. The 10 × ’20 initiative calls for the development of 10 novel, safe and effective, systemic antibiotics by 2020. Forty-five public health organizations and professional societies across the spectrum of medicine, including the American Medical Association and American Academy of Pediatrics, have endorsed the 10 × ’20 initiative [58]. Aside from the short term goal of increasing availability of critically needed new antibiotics, the underlying theme of 10 × ’20—akin to Dr. Lederberg’s warning about the future of human-microbe relations—is the need to establish an infrastructure that recognizes and responds to ongoing changes in antibiotic resistance and facilitates antibiotic R&D in perpetuity.” Infectious Diseases Society of America 2011.

“IDSA is calling for a $500 million annual increase in Congressional appropriations to support an expansion of NIAID’s budget in the area of antibiotic resistance and antibiotic discovery research. As discussed previously [46], NIAID is aware of the need for additional research to address the antimicrobial, and particularly antibiotic, resistance problem. However, the overall flat budget of NIH and NIAID limits the Institute’s ability to sufficiently increase funding for critically needed new research in antibiotic resistance and development, [103] as elaborated above.” Infectious Diseases Society of America 2011.

“IDSA strongly supports enactment of PAMTA and the adoption of comparable measures (including FDA Center for Veterinary Medicine [CVM] regulations) to stop the use of antibiotics for growth promotion, feed efficiency, and routine disease prevention purposes in animal agriculture. IDSA also supports requiring prescriptions and veterinary oversight of all antibiotics given to animals. Antibiotic use in agriculture, similar to human medicine, should be carried out under the supervision of a veterinarian, within the boundaries of a valid veterinarian-client-patient relationship. In addition, FDA/CVM should: 1) define procedures for antibiotic administration in animals that will permit short-term antibiotic use for those animals that have a current therapeutic need or an immediate prophylactic need due to an infectious outbreak in surrounding animals where such animal has been exposed or is highly at risk for exposure to disease; and 2) work with CDC and USDA to expand post-approval surveillance under NARMS (see recommendation IV.2). As discussed in recommendation IV.3, the amount and type of antibiotics used in animal feed should be tracked and made publicly available on an annual basis. In addition, ongoing risk analysis is needed to better understand the impact of the remaining uses of antibiotics in animal agriculture on human and animal health (see recommendation VIII.3).” Infectious Diseases Society of America 2011.

“What are possible approaches to addressing this problem? Incentivize the creation of new antibiotics. It is well accepted that there are still new antibiotics to be discovered; this is not the limiting factor. The challenge is in improving the drug development process, from discovering new chemicals that could make good antibiotics, to identifying new ways of targeting bacteria, to creating better mechanisms for studying antibiotics in people during clinical trials. Pew was a key player in the Generating Antibiotic Incentives Now (GAIN) Act, which was passed by Congress in 2012. The act provides additional market protection and expedited FDA application review for certain new antibiotics. There has been significant interest in using the provisions of the legislation: companies have already applied for 12 different antibiotics to be included under its provisions. There was some opposition to the act because it was seen as benefitting the pharmaceutical industry by adding market protections, which would increase profits for companies. On the other hand, there were pharmaceuticals companies that wanted the act to go further, by including more new antibiotics or changing the FDA approval process. Pew worked with the major stakeholders to create an acceptable compromise. Pew was involved in both crafting and advocating for the bill with policymakers. The act was added on as a component of a much larger piece of FDA legislation, which passed with overwhelming support. Most new drugs have been produced in the US and the EU, but as China and India develop their own biopharmaceuticals research sector, they may play a larger role. Improve stewardship of existing drugs. More evidence is needed for what stewardship strategy (optimal management of antibiotic use) would work best in the US. Once there is strong evidence for a certain stewardship strategy, the path to implementation may become clearer. In many other parts of the world, antibiotics are sold over the counter and much more freely used than in the US. Recently, China has set targets for reducing antibiotic use and India has begun to require prescriptions for many previously over-the-counter antibiotics. Counterfeit and substandard drugs, more prevalent in the developing world, are a serious problem that contributes to antibiotic resistance.” Notes from a conversation with Allan Coukell and Nicole Mahoney of the Pew Charitable Trusts, 7/17/2013

6.“Using Modified Plasmids to Suppress Antibiotic Resistant Pathogens” Roe 2011

7.“The CDC’s Get Smart program serves as an important starting point for implementation of antimicrobial stewardship programs. Tools available through the Get Smart program target health care providers and patients. Increased resources are needed so that CDC can: 1) conduct primary research to define effective communications strategies to inform the public and physicians about inappropriate antimicrobial use; and 2) expand Get Smart, improve CDC’s educational tools, and allow for a more effective public dissemination campaign.” Infectious Diseases Society of America 2011.

8.“Extraordinary work on the prevention side is necessary, including significant investment in infrastructure before emergency strikes. Potential philanthropic opportunities in this area may involve supporting studies to determine the most cost-effective strategies for prevention, which could then be applied to save resources in the long run. Prevention is effectively local, and because of the risk of resistance developing in one region before spilling over to another, the local level is essential for broader safety. One particularly important prevention strategy is to ensure that antibiotics are used only when necessary, and, when necessary, are used appropriately, in order to slow the development of AR. Another response focuses on measures to prevent spread of the antimicrobial resistant diseases from one individual to another. In hospitals, this means infection control; in other contexts, it may be accomplished by using immunizations or good personal hygiene. The interventions in these areas would be education campaigns in the community around better hygiene and awareness of the risks of antibiotics. Although drug development alone cannot fully address the problem of AR, developing new models for investment and development of new antimicrobials is essential. Though there are some drugs in the pipeline right now, but that pipeline needs to be fully re-stocked for the long term. Although not a solution in the short-term, vaccines could be highly impactful interventions. For instance, the introduction of a vaccine for the bacteria causing pneumococcal pneumonia has helped reduce the incidence of AR in those infections” Notes from a conversation with Steve Solomon and Jean Patel of the Centers for Disease Control and Prevention, 6/18/2013.

9.Peters et al. 2008, pg. 1087. Though note that this budget also includes research on non-bacterial agents: “Regarding research specific to issues involving antimicrobial resistance, Peters et al. indicate that NIAID is currently spending more than $200 million. In considering this amount, it is important to recognize that it also includes support for research on resistance to antiviral (including HIV), antifungal, and antiparasitic (including antimalarial) agents. Within the bacterial category, research on resistance to drugs targeting Mycobacterium tuberculosis is included. It is not possible to tease from this analysis the level of commitment NIAID has made to the study of resistance in the ESKAPE bugs.” Rice 2008.

10.“Duke University, Durham, N.C., has been awarded $2 million to initiate a new clinical research network focused on antibacterial resistance. Total funding for the leadership group cooperative agreement award could reach up to $62 million through 2019. Funding is provided by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. ‘Antibacterial resistance is a serious and growing public health threat that is endangering the global medical community’s ability to effectively treat conditions ranging from simple skin infections to tuberculosis,’ said NIAID Director Anthony S. Fauci, M.D. ‘Through this new clinical research network, we will strengthen our existing research capacity and address the most pressing scientific priorities related to antibacterial resistance.’” NIH 2013.

11.“Four of CDC’s eight National Centers conduct work related to antimicrobial resistance; these activities fall within a number of different budget lines.” Notes from a conversation with Steve Solomon and Jean Patel of the Centers for Disease Control and Prevention, 6/18/2013.

12.“Pew was a key player in the Generating Antibiotic Incentives Now (GAIN) Act, which was passed by Congress in 2012. The act provides additional market protection and expedited FDA application review for certain new antibiotics. There has been significant interest in using the provisions of the legislation: companies have already applied for 12 different antibiotics to be included under its provisions. There was some opposition to the act because it was seen as benefitting the pharmaceutical industry by adding market protections, which would increase profits for companies. On the other hand, there were pharmaceuticals companies that wanted the act to go further, by including more new antibiotics or changing the FDA approval process. Pew worked with the major stakeholders to create an acceptable compromise. Pew was involved in both crafting and advocating for the bill with policymakers. The act was added on as a component of a much larger piece of FDA legislation, which passed with overwhelming support.” Notes from a conversation with Allan Coukell and Nicole Mahoney of the Pew Charitable Trusts, 7/17/2013

13.“Innovative Medicines Initiative (IMI) is a public-private partnership composed of representatives from the pharmaceutical industry, universities, and some European organizations that are working on antibiotic resistance. IMI is funded by the European Union and the European pharmaceuticals industry. Until recently, this group has focused on basic science and clinical trials. It has now expanded to working on creating business models for antibiotics that provide a sufficient return on investmentwhile also promoting good stewardship, and to assessing the societal value of antibiotics.” Notes from a conversation with Allan Coukell and Nicole Mahoney of the Pew Charitable Trusts, 7/17/2013

14.Infectious Diseases Society of America, “Antibiotic Resistance”

15.Notes from a conversation with Allan Coukell and Nicole Mahoney of the Pew Charitable Trusts, 7/17/2013

16.Alliance for the Prudent Use of Antibiotics, “Homepage”

17.“Doctors depend on antibiotics to treat illnesses caused by bacteria, from pneumonia to meningitis and other life-threatening infections. The effectiveness of many antibiotics has begun to wane, the legacy of decades of unnecessary overuse in both human medicine and agriculture. Keep Antibiotics Working is a coalition of health, consumer, agricultural, environmental, humane and other advocacy groups with more than eleven million members dedicated to eliminating a major cause of antibiotic resistance: the inappropriate use of antibiotics in food animals.” Keep Antibiotics Working, “Homepage”.

18.Notes from a conversation with Steve Solomon and Jean Patel of the Centers for Disease Control and Prevention, 6/18/2013.

19.Notes from a conversation with Allan Coukell and Nicole Mahoney of the Pew Charitable Trusts, 7/17/2013