Newsletter Vol. 30 No. 1


Related Initiatives to Spur Antibiotic Development

APUA and ReAct advise new WHO book on antimicrobial resistance
New U.S. FDA guidances on antibiotic use in food animals: mixed reviews
UK-based Antibiotic Action Initiative
BARDA awards $67 million contract to Tetraphase to develop novel antibiotic
April 2012 issue of
Infection Control and Hospital Epidemiology dedicated to antimicrobial stewardship
 



Dr. Stuart Levy and Dr. Otto Cars advise new WHO book on antimicrobial resistance

Dr. Stuart Levy (APUA President) and Dr. Otto Cars (Executive Director of ReAct) coauthored a chapter and contributed their expert opinions on measures to ensure better access to antibiotics in the World Health Organization’s (WHO) latest book, “The Evolving Threat of Antimicrobial Resistance – Options for Action.” Dr. Cars stated that “WHO’s ambitious global plan [to contain antimicrobial resistance] could truly be informed by the content of the book.”

Launched in Geneva on March 8, the open-access book (available for download from the ReAct website) builds on recommendations from the 2001 WHO Global Strategy for Containment of Antimicrobial Resistance and is the result of collaboration between WHO and 50 international experts in the field. The book aims to raise awareness and stimulate coordinated efforts by describing various global policy activities that have addressed antimicrobial resistance and preservation of medicine efficacy in infectious disease.

A few of the most notable case studies of successful actions taken by governments, healthcare facilities, and providers to slow development of resistance include:

  • A program in Thailand that reduced antibiotic prescriptions by up to 46% while maintaining treatment efficacy at 97%;
  • A program in Vietnam to regulate antibiotics more strictly for treatment of acute respiratory infections;
  • The reduction of antibiotic use in farmed fish in Norway by 98% between 1987 and 2004, by the effective use of vaccines; and
  • Bringing antimicrobial stewardship and rational use of medicines to the forefront of medical education in medical universities and graduate schools around the world.

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New U.S. FDA guidances on antibiotic use in food animals: mixed reviews

On April 11, 2012, the FDA issued three long-awaited documents containing their strategy for regulating antibiotic use in food animal production – final Guidance #209, draft Guidance #213, and the draft of proposed Veterinary Feed Directive regulation. Draft Guidance #213 and the draft Veterinary Feed Directive regulation are open for public comment until July 12, 2012, after which final versions will be drawn up.

Final Guidance #209, also known as “The Judicious Use of Medically Important Antimicrobial Drugs in Food-Producing Animals,” recommends that food animal producers phase out the use of medically important drugs for growth promotion or feed efficiency purposes. It also recommends phasing in, over a period of three years, veterinary oversight of all medically important drugs being used in therapeutic situations (which include disease treatment, control, and prevention).

Draft Guidance #213 is called “Recommendations for Drug Sponsors for Voluntarily Aligning Product Use Conditions with Guidance for Industry #209.” It calls on drug companies to comply with Guidance #209 by removing any uses associated with growth promotion from the ones listed on their products’ FDA-approved labels. Within three months of issuance of the final Guidance #213, the companies will have the option of applying to list therapeutic uses (including disease treatment, control, and prevention) on their products’ FDA labels instead. After three years the FDA plans to evaluate how many companies have adopted Guidance #213, and how long it took them to do so, as they consider their next actions.

The draft regulation of the Veterinary Feed Directive program proposes establishing broad veterinary oversight of all drug use in animal feed, with clearly outlined ways in which veterinarians can authorize the use of drugs in certain situations. Such regulation would be necessary to make the veterinary oversight component proposed in Guidance #209 possible.

The FDA’s issuance of these guidances has stirred up many differing opinions concerning their feasibility and effectiveness. The FDA has acknowledged that the voluntary aspect of the guidances is a limitation. However, the FDA also claims that enforcing an outright ban on nontherapeutic antibiotic use in food animal production would require a long-winded formal process, in which drug companies would have the opportunity to demand evidentiary hearings to try to prove the safety of their products – in sum, that decades would pass before any real action could happen. In that sense, voluntary recommendations – while not as far-reaching and effective as could be desired – might at least start the process of achieving the desired goals.

Other organizations’ opinions about the guidances fall into three broad camps. The most negative opinion holds that the FDA guidances are tragically flawed, empty gestures for not requiring the food animal industry to take action. The guidances could also be seen as going against the decision made by the court in March that penicillin and tetracycline use in food animal production is in fact unsafe, and that the FDA must uphold the proposed ban against them. Another concern has been raised that if the industry does not even obey the law (as was seen when traces of banned fluoroquinolones were found in chicken feathers), how can producers be expected to comply with voluntary recommendations? The sheer volume of antibiotic use in animals (accounting for 80% of all antibiotics sold in the U.S.) can only be reduced through cooperation from the entire industry. The organizations that take this attitude (including the NRDC and the Center for Science in the Public Interest) insist that a more productive move would be for the FDA to support the Preservation of Antibiotics for Medical Treatment Act, which was introduced in Congress in 2009.

Groups like Keep Antibiotics Working, and Congresswoman Louise Slaughter of New York, the author of PAMTA legislation, hold a more neutral position. While they commend the FDA for recognizing the seriousness of problems posed by unregulated antibiotic use and for taking a step in the right direction, they are skeptical that the step will lead to tangible results in the near future. Slaughter calls the FDA’s pace “nothing short of glacial.” They criticize the lack of a plan for monitoring drug use under the guidances, which is necessary as a measure of their effectiveness.

In the third camp, organizations including APUA, the Pew Charitable Trusts, and the American Academy of Pediatrics applaud the guidances as an important step forward and call on major drug companies and food producers to comply with them. In a press release through Elsevier Global Medical News, Dr. Stuart Levy of APUA states “These voluntary FDA guidances will hopefully promote leadership by the large food producers to reduce antibiotic overuse on the farm, but there is a need for strong monitoring of their implementation.” The Pew Charitable Trusts also commends the FDA for “the most sweeping action the agency has taken in this area,” but warns that “if these measures do not bring down antibiotic use and drug-resistant bacteria, then FDA will have to take additional steps.”

Find the full text of final Guidance #209, draft Guidance #213, and draft VFD regulation at www.fda.gov.

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UK-based Antibiotic Action Initiative

Antibiotic Action was launched in 2011 to provide a global platform from which to inform all about the need for discovery, research and development of antibiotics. Antibiotic Action calls for immediate action to ensure replenishment of the pipeline of new antibacterial agents. The initiative is clear that the time for discussion is over and that the time for action is now, and with the tagline “Determined to Succeed,” Antibiotic Action is calling on colleagues across the world to help ensure it does.

Two recent articles published in The Lancet [1] and Nature Reviews Microbiology [2] present overviews of the pending crisis of no new antibiotics, and say more about the need for Antibiotic Action than can be reported here.

The initiative is directed by Professor Laura Piddock, Professor of Microbiology at the University of Birmingham, UK and has received considerable support from professional societies and charities from around the world. A major mechanism for stimulating political activities has been the petition on the website. This remains open and as a tool to maintain pressure on governments, policy makers and national agencies to address the various issues in antimicrobial chemotherapy and not just re-generate antibacterial drug discovery, research and development.

Antibiotic Action’s long term aspiration is the establishment of a public-private global alliance to meet its aims, and particularly a model by which antimicrobial development can be successfully taken forward. There is no intention to “reinvent wheels,” but rather to capitalize on or adapt those that are already in existence, such as the models employed by the GAVI Alliance and Bill & Melinda Gates Foundation for the successful delivery of vital vaccines worldwide. 

APUA is coordinating with the Antibiotic Action Initiative to strengthen our efforts and assist WHO in implementing their new global plan. We are now inviting all members of APUA to promote Antibiotic Action and ask their colleagues, friends and family to visit www.antibiotic-action.com and sign the petition now. If you wish to promote Antibiotic Action nationally or globally or become an Antibiotic Action Champion, please contact Tracey Guise at tguise@bsac.org.uk.

References
1. Piddock LJV. Lancet Infect Dis 2011 Nov 17
2. Bush K, Courvalin P, Dantas G et al. (2011) Tackling antibiotic resistance. Nature Reviews Microbiology 9(12):894-6.

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BARDA awards $67 million contract to Tetraphase to develop novel antibiotic

The Biomedical Advanced Research and Development Authority (BARDA) of HHS is now more than ever taking on the burden of funding novel antibiotic drug development. On February 16, 2012, BARDA chose Tetraphase Pharmaceuticals to be awarded a contract for up to $67 million. Tetraphase specializes in developing antibiotics against pathogens that are resistant to other drugs. The lead product candidate in their clinical pipeline is TP-434, an antibiotic against a broad spectrum of multidrug-resistant Gram negative pathogens that is currently in Phase II clinical trials. TP-434 could potentially be an empiric, once-daily antibiotic against pathogens such as Bacillus anthracis and Yersinia pestis, and it is hoped that is will also be a therapeutic agent against serious healthcare-associated infections.

In combination with funding from other federal sources, funding for TP-434 could reach $100 million. The BARDA contract exemplifies the type of funding commitment necessary to supplement legislation like the GAIN Act and PDUFA if antibiotic development is to be significantly incentivized. Past BARDA awardees that manufacture antibiotics include Achaogen, who develop broad-spectrum antibiotics against potential bioterrorism pathogens; Elusys Therapeutics, the makers of an anthrax anti-toxin; and GlaxoSmithKline, which focuses its pipeline on bioterrorism pathogens, ventilator-associated pneumonia, and abdominal infections. Find out more about this award in the Tetraphase press release.

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April 2012 issue of Infection Control and Hospital Epidemiology dedicated to antimicrobial stewardship

Dr. Neil Fishman (Associate Chief Medical Officer for the University of Pennsylvania Health System) and Dr. Arjun Srinivasan (Associate Director for Healthcare Associated Infection Prevention Programs at the CDC) were guest editors for the April 2012 issue of Infection Control and Hospital Epidemiology, the first ICHE issue focused entirely on antimicrobial stewardship. The issue advocated for making antimicrobial stewardship maximally effective through powerful, immediate interventions that will improve quality of care and reduce wasteful healthcare spending. In a companion post on the CDC blog "Safe Healthcare," Dr. Fishman applauded growing recognition of the vital nature of antimicrobial stewardship in hospitals nationwide, but pointed out that "truly effective stewardship means more than just an acknowledgement of its importance."

The 24 articles in the April issue of ICHE present a “snapshot” of the current state of the science in antimicrobial stewardship. Some articles addressed the financial impacts of antimicrobial stewardship business models. Stewardship programs, after all, represent a unique type of healthcare quality initiative that improves both clinical and institutional outcomes, as opposed to many other programs that increase the cost of care. Standiford et al. conducted a study entitled “Antimicrobial stewardship at a large tertiary care academic medical center: cost analysis before, during, and after a 7-year program” at the University of Maryland Medical Center. During its seven year existence, the antimicrobial stewardship program described in the paper made possible a 46% decrease in antibiotic expenditures. These costs increased again by 32% within two years of terminating the program, mostly due to resurgence in the use of broad-spectrum antibiotics. Total unnecessary costs in those two years amounted to $2 million. This case study provides a cautionary tale against eliminating stewardship programs, and may serve as a useful model for institutions implementing them.

Other articles focused on the need for stewardship programs to reflect the broadening of medical practice by including not only adult acute-care settings, but also outpatient and post-discharge therapy, transitions in care, long-term institutions, pediatric facilities, and intensive care settings. And despite many advances in stewardship program implementation, some articles pointed out room for improvement and for further data collection – especially in the “low-hanging fruit” areas such as the parenteral-oral conversion for fluoroquinolones. Cosgrove et al. also gave an account of a first-of-its-kind multicenter trial of an antimicrobial stewardship intervention initiated by the CDC Prevention Epicenter. The results of the trial emphasized the benefits of performing both large-scale, multicenter studies, and smaller, simpler trials.

A joint policy statement from SHEA, IDSA, and PIDS outlined recommendations for a national approach to antimicrobial stewardship. These included adopting economic incentives and new regulatory approaches to encourage antimicrobial development, enhancing surveillance systems, investing in diagnostic development, and eliminating the non-judicious use of antibiotics in plants and animals. A position paper from SHEA and APIC focused on multidrug-resistant organisms as a grave threat to patient safety by causing a significant proportion of HAIs, and highlighted the need for collaboration between epidemiologists and infection preventionists.

More information on APUA’s advocacy of antibiotic stewardship can be found in the APUA Clinical Newsletter Vol.29 No.3 (“Enhancing Infection Control with Antibiotic Stewardship”) and Vol.29 No.1 (“Antibiotic Stewardship Gaining Traction: Recommended Models and Resources”). See also the April issue of ICHE, and Dr. Neil Fishman’s CDC blog post.

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