AAC Accepts, published online ahead of print on 27 May 2014 Antimicrob. Agents Chemother. doi:10.1128/AAC.02623-14 Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Eight More Ways To Deal with Antibiotic Resistance

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Authors: Matthew Metz1,2,* and David M. Shlaes3

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Affiliations: 1DuPont Pioneer, Johnston, IA, [email protected] 2Previously with the US Department of Health and Human Services, Biomedical Advanced Research and Development Authority, Broad Spectrum Antimicrobials Program, Washington, DC

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3Anti-Infectives

Consulting LLC, Stonington, CT, [email protected]

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* Statements in this piece are those of the author and not positions or endorsements of DuPont or the US Government.

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(The views expressed in this Commentary do not necessarily reflect the views of the journal or of ASM.)

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Abstract: The fight against antibiotic resistance must be strengthened. We propose actions US Government agencies and private sector entities can take to build a more comprehensive effort. These actions can increase the viability of investing in new antibiotics, assure the quality and stewardship of all antibiotics, and make responses to emerging resistance more informed. Success requires thoughtful exercise of Federal authority, and firm commitment to share data and the value generated with new, life-saving antibiotics.

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Key Words: antibiotic resistance, antibiotic stewardship, clinical trials, data disclosure, valuebased pricing.

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Main Text:

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There is an increasing and warranted sense of urgency to reverse the public health

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problem of antibiotic-resistant infections. Antibiotic-resistant infections are becoming more

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frequent culprits in treatment failures and escalating healthcare costs. For 2013, the US Centers

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for Disease Control and Prevention (CDC) estimated that in the US alone, over 2M people were

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impacted by antibiotic-resistant infections, with at least 23,000 deaths resulting (1). These

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statistics are both likely underestimates, and limited to a small segment of the global population

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that is exposed to antibiotic-resistant bacteria. Prominent experts in the field, Bartlett, Spellberg,

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and Gilbert proposed, “8 Ways to Deal with Antibiotic Resistance” (2) recommending goals for 1

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the healthcare and pharmaceutical development communities. These goals included: diligence in

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the appropriate use of antibiotics (stewardship); more effective infection control; development of

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medical diagnostics to prevent inappropriate antibiotic therapy; and stimulating renewed

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development of new antibiotics.

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To reverse the regression to medicine without effective antibiotics there must be

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concerted efforts to attack the problem from all angles, and by many more parties. Actions must

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combat the spread of antibiotic resistance, reinvigorate development of new antibiotics, and

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prolong the effectiveness of current and new antibiotic therapies. Therefore, we offer eight

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additional actions that the US Government and the private sector can take to combat antibiotic

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resistance:

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1.

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significantly reduce the uncertainty that discourages drug developers from pursuing new

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antibiotics. A large hurdle to approval of new antibiotics is the determination of just how great

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the clinical effect must be. Non-inferiority trials can end up having prohibitively large enrollment

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requirements. Availability of robust and uniform historical controls to measure treatment effects

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against would greatly simplify study design, and remove some of the uncertainty that drug

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developers face. The FDA has accumulated numerous and varied data sets on clinical outcomes

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of infections under different treatment scenarios, including those with pharmacometric data.

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These data are available to drug developers only in fragmented, often proprietary records. The

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FDA should make these data useful to current drug development efforts by conducting and

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publishing a meta-analysis deriving historical control outcomes of different infections and under

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different conditions. The FDA should continue to build on the progress it has made in the last

Reduce Clinical Trial Uncertainty. The US Food and Drug Administration (FDA) can

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few years towards using this analysis to establish clear, feasible and uniform expectations of

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clinical effectiveness across the field of antibiotic indications. This would significantly reduce

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risks antibiotic developers face in trying to establish primary outcome expectations in clinical

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trials.

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2.

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Agriculture (USDA) can catalyze market forces that will reduce prolific agricultural use of

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antibiotics. The USDA has instituted certification of consumer products to set standards specific

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to industry practices and enable these to be recognized by consumers. Certifications such as

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“USDA Prime” for beef products (3), and “Organic” and “Biobased” on a wide range of

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commodities (4,5) have as a side effect created labels with market value. The USDA should

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exercise this certification authority and create a “No Feed-Antibiotics” label to provide

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consumers with the same ability to discriminate food products that have been produced without

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growth-promoting antibiotics. Antibiotic use in agriculture is recognized as a contributor to

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increasing antibiotic resistance (6). Public awareness of this problem is sufficient to strengthen

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market incentives against the still prolific use of antibiotics in agriculture when combined with a

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widely recognized certification.

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3.

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Agency (EPA) can require manufacturers of antibiotics for agricultural use to generate data on

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public health and environmental consequences of this use, and can set limits on antibiotic use

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based on this data. The EPA has a long history of exercising its authority under the Federal

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Insecticide, Fungicide and Rodenticide Act (FIFRA, 7) to regulate residues from antimicrobial

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fungicides in agricultural products and released into the environment from farming. FIFRA

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requires pesticide manufacturers to register their products with EPA before they can be marketed

Boost Market Value for Not Feeding Animals Antibiotics. The US Department of

Strengthen Regulation of Farm-Feeding Antibiotics. The US Environmental Protection

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for agricultural use. The EPA should explore requiring FIFRA registration of antibiotics used in

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food animal production. Data requirements for registration will help focus and support the

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restricted use that is important for deterring selection of antibiotic resistance in the food supply,

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and in the environment due to farm antibiotic effluents. Registration under FIFRA requires the

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generation of data on concerns such as “environmental fate” and dietary and non-dietary hazards

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to humans. Further, registrations granted under FIFRA stipulate the limitations and conditions

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under which registered chemicals can legally be used.

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Recent research reveals association between resistance in agricultural, environmental,

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and community settings (8), and even indicates movement of antibiotic resistance through the

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food supply into the community (9,10). At the same time, there is new data on Salmonella

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indicating that distinct populations of antibiotic-resistant bacteria can exist largely segregated in

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human and farm animal populations (11). More extensive data on antibiotic-resistant zoonoses,

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and regulation of antibiotic use in animal husbandry based on such data is needed to stem the

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contribution of agricultural practices to antibiotic resistance. An example of the much needed

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data that could come from closer study is the degree to which clinically-relevant antibiotic

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resistance genes may hitchhike on mobile genetic elements with the one(s) under selection.

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Mobile genetic elements are well known to simultaneously carry multiple resistance genes

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against widely varying antibiotics (12).

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The FDA recently released Guidance for Industry #213, which seems unlikely to reduce

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the impact on resistance development of antibiotic use as growth promoters in farm animal

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production. The guidance focuses on eliminating growth promoting use of just “medically

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important” antibiotics (13), which will not close the gate on collateral selection for resistance

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against these, when genetically linked resistance elements to other antibiotics is still under

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selection. Further, the guidance is a non-binding recommendation that antibiotic manufacturers

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remove all claims on drug labels of growth-promoting effects in farm animals. For the

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manufacturers that follow this recommendation, misuse of their products will be illegal and

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punishable with fines and sanctions. But, drug manufacturers that do not change their labels will

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remain legal sources of growth-promoting antibiotics, and may well take over market-share from

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those manufacturers who do follow the guidance. The problem of antibiotic use in agriculture accelerating resistance development in

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human infections now looks more likely to be tackled by the EPA than by the FDA. The

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interpretation of EPA’s FIFRA authority has been extended so far as to be applied to insecticidal

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proteins in genetically engineered plants. Given the negative public health consequences of

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improper and excessive agricultural use of antibiotics, FIFRA should reasonably be extended

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into this arena.

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coordination of efforts by the various federal agencies that have a role in combatting antibiotic

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resistance. An ongoing US Government working group, the Interagency Taskforce for

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Antimicrobial Resistance (ITFAR), has been working to communicate federal efforts related to

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combatting antibiotic resistance (14). The ITFAR has to date succeeded in sharing information

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among various agencies from the US Department of Health and Human Services (CDC, FDA,

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NIH, the Centers for Medicare and Medicaid Services, the Biomedical Advanced Research and

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Development Authority, and others), the US Departments of Agriculture, Defense, and Veterans

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Affairs, and the EPA. The ITFAR should be given more authority so that it not only provides

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participating agencies and the public visibility into what different agencies are doing to combat

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antibiotic resistance, but also can require agencies to make commitments as to future actions and

Unify US Government Efforts. The President of the United States can require

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prioritization of activities to combat antibiotic resistance. This centralized influence over US

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Government planning and prioritization will best be instituted by an executive order. The

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President of the United States should give the ITFAR the authority to harmonize and focus US

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federal agencies’ efforts at combatting antibiotic resistance.

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remove disincentives to sharing information, prior to publication, when there are public health

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threats such as emerging antibiotic resistance. Typically, researchers closely guard data about

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new discoveries until amassing enough data and analysis for publication. In the case of the

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infamous NDM-1 antibiotic resistance gene, almost a year intervened between its discovery, and

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the knowledge of its existence being made public (15). In the intervening time, the tools for

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detecting and controlling its spread remained undeveloped while it crept across various

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continents. Journal editors need to exercise their authority over the publication process and

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incentivize early release of data that is critical to public health efforts like understanding and

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containing antibiotic resistance. Part of the delay in release of information results from the

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publication process itself – in the case of NDM-1 the original article was submitted in June,

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2009, and only published in December, 2009. Rapid publication and open online access are

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existing mechanisms of accelerating the dissemination of information, but these are insufficient

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to offset the belated release of information driven by publication pressures, and the insistence of

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journal editors that information in manuscripts be left uncommunicated ahead of publication.

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Journals could alleviate this problem by establishing policies of giving priority to: a) publication

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of full analyses of data previously released publicly in preliminary form to accelerate public

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health responses; and b) publication of such analyses by the originators of the data. Doing this,

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rather than turning away authors for presenting data that will not have been seen for the first

Incentivize Early Sharing of Data. Publishers of peer-reviewed, scientific journals can

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time, will alleviate the prisoner’s dilemma that scientists face. The disclosure of the data for the

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benefit of public health prior to it being in a manuscript would no longer be penalized with

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diminished chances of publication or risk of others racing ahead with a preemptive publication

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analyzing the disclosed data.

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6.

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antibiotics to the same standards of drug potency as the name-brand manufacturers. Drug

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regulators allow generic drugs to enter the market with relative leniency applied to how much

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they must perform like their name-brand progenitors. This feature of likeness is termed

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bioequivalence. The FDA’s guidance to industry for generic antibiotics recommends exposures

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within a 90% confidence interval of the branded version. This threshold is not assured, as the

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vast majority of the FDA guidance documents for specific generic antibiotics are draft and non-

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binding (16). Furthermore, since the recommended studies make no specifications for

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pharmacokinetic (PK) properties, studies with very limited PK sampling in terms of population

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size and time points could easily overlook inadequate drug exposure levels. This level of

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flexibility is not appropriate for antibiotic dosing. Under dosing antibiotics is one way to

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accelerate resistance development. Regulators need to more earnestly gather data on cases where

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generic antibiotics perform less effectively than name-brand versions (studies on this topic vary

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widely) and should use this evidence to establish a more appropriately stringent bioequivalence

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requirement for generic antibiotics. This will raise the quality of the generic antibiotics

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frequently used to treat infections and cut chances of inadequate dosing.

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same standards to antibiotics seeking new approvals as those that are currently generic, and

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alleviate this particular disincentive for antibiotic development. Antibiotics currently on the

Assure the Quality of Generic Antibiotics. The FDA can hold manufacturers of generic

Level the Playing Field between New and Old Antibiotics. The FDA can apply the

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market and in generic form ride on approvals granted with much less stringent requirements than

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those imposed upon antibiotics seeking regulatory approval today. The FDA should equalize

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labeling standards for generics and name-brand antibiotics, such that a new antibiotic does not

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require more information on its label than is required of a generic currently in use for the same

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indication. Two new movements by the FDA signal an encouraging change in this direction: one

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would allow generic manufacturers to change their safety labeling (17); the second would allow

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label changes that incorporate antibiotic susceptibility breakpoints supported by modern PK data

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(18). A more inclusive approach to label changes removes the conundrum having to work with a

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brand manufacturer when none exists, and provides more speed and flexibility to get safety

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labeling out to physicians and patients. Regular review of the antibiotic susceptibility

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breakpoints for generic antibiotics must be carried out. Having modern breakpoint data on both

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old and new antibiotics will better inform regulatory decisions about the relative risk and benefit

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of a new approval, as well as guide better treatment decisions in the clinic. Asymmetric

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standards should no longer place new antibiotics at a disadvantage against the failing old

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antibiotics we require replacements for.

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costs (e.g. Medicare and insurance companies) can incentivize developers of new antibiotics by

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promising them a share of the savings that will be realized with effective treatments. Antibiotic

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resistant infections in the US can be blamed for millions of illnesses and thousands of deaths

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annually. Not only is this a dreadful burden of morbidity and mortality, but with estimated

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additional per-patient costs of $18-29,000 based on a recent study in the US (19), it is a hefty

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direct financial burden on the healthcare system. An earlier study published in 2003 found

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MRSA infections to increase the cost of hospitalizing patients by $13,000 compared to

Assure value-based pricing of new antibiotics. Public and private payers of healthcare

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susceptible infections (20), suggesting that the cost has been growing. New antibiotics that

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overcome existing resistance clearly have the capacity to save lives and resources that would

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otherwise be lost to untreatable infections. To date, there has not been a scheme to reward

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antibiotic developers for the value that new drugs of this class will accrue to the healthcare

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system. Value-based pricing has been proposed (21) as a way to recognize this value and pay

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pharmaceutical developers proportionally to healthcare costs that are saved when an otherwise

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untreatable infection is rendered treatable. Public and private healthcare payers should develop

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and commit to a scheme for value-based pricing of new antibiotics. If developers can anticipate

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being paid a portion of the savings that their products create in the healthcare system, antibiotic

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development will become a more viable investment.

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Antibiotic resistance is a serious public health problem that is continuing to grow and

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outpace the development of new, effective antibiotics. This problem will only be brought under

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control through a holistic and comprehensive set of actions involving many responsible parties.

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We offer specific actions that US Government agencies and private sector entities can take to

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improve antibiotic stewardship and revitalize antibiotic development.

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References:

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4. US Department of Agriculture. http://www.ams.usda.gov/AMSv1.0/nop. 5. US Department of Agriculture. http://www.biopreferred.gov/. 6. American Academy of Microbiology. 2009. Antibiotic Resistance: An Ecological Perspective on an Old Problem (academy.asm.org/index.php/environmental-microbiologyecology-evolution/473-antibiotic-resistance-an-ecological-perspective-on-an-oldproblem). 7. US Environmental Protection Agency. www.epa.gov/agriculture/lfra.html. 8. Forsberg KJ, Reyes A, Wang B, Selleck EM, Sommer MO, Dantas G. 2012. The shared antibiotic resistome of soil bacteria and human pathogens. Science. 337:1107-1111. 9. Kluytmans JA, Overdevest IT, Willemsen I, Kluytmans-van den Bergh MF, van der Zwaluw K, Heck M, Rijnsburger M, Vandenbroucke-Grauls CM, Savelkoul PH, Johnston BD, Gordon D, Johnson JR. 2013. Extended-spectrum β-lactamase–producing Escherichia coli from retail chicken meat and humans: comparison of strains, plasmids, resistance genes, and virulence factors. Clin Infect Dis. 56:478-487. 10. Harrison EM, Paterson GK, Holden MT, Larsen J, Stegger M, Larsen AR, Petersen A, Skov RL, Christensen JM, Bak Zeuthen A, Heltberg O, Harris SR, Zadoks RN, Parkhill J, Peacock SJ, Holmes MA. 2013. Whole genome sequencing identifies zoonotic transmission of MRSA isolates with the novel mecA homologue mecC. EMBO Molec. Medicine. 5:509-515. 11. Mather AE, Reid SW, Maskell DJ, Parkhill J, Fookes MC, Harris SR, Brown DJ, Coia JE, Mulvey MR, Gilmour MW, Petrovska L, de Pinna E, Kuroda M, Akiba M, Izumiya H, Connor TR, Suchard MA, Lemey P, Mellor DJ, Haydon DT, Thomson. NR. 2013. Distinguishable epidemics of multidrug-resistant Salmonella typhimurium dt104 in different hosts. Science. 341:1514-1517.

12. H. Nikaido. 2009. Multidrug resistance in bacteria. Annu. Rev. Biochem. 78:119-146. 13. US Food and Drug Administration. 2013. Guidance for Industry# 213 New Animal Drugs and New Animal Drug Combination Products Administered in or on Medicated Feed or Drinking Water of Food-Producing Animals: Recommendations for Drug Sponsors for Voluntarily Aligning Product Use Conditions with GFI #209 (www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/Guidance forIndustry/UCM299624.pdf). 14. US Centers for Disease Control and Prevention. 2013. (www.cdc.gov/drugresistance/actionplan/taskforce.html). 15. Yong D, Toleman MA, Giske CG, Cho HS, Sundman K, Lee K, Walsh TR. 2009. Characterization of a new metallo-β-lactamase gene, blaNDM-1, and a novel erythromycin esterase gene carried on a unique genetic structure in Klebsiella pneumoniae sequence type 14 from India. Antimicrob Agents Chemother. 12:5046-5054. 16. US Food and Drug Administration. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm0 75207.htm. 17. US Food and Drug Administration. 2013. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm374171.htm 18. US Food and Drug Administration. 2013. FDA Anti-Infective Drugs Advisory Committee. (October 17, 2013 meeting; http://www.fda.gov/AdvisoryCommittees/Calendar/ucm364149.htm). 19. Roberts RR, Hota B, Ahmad I, Scott RD 2nd, Foster SD, Abbasi F, Schabowski S, Kampe LM, Ciavarella GG, Supino M, Naples J, Cordell R, Levy SB, Weinstein RA. 2009.

Hospital and societal costs of antimicrobial-resistant infections in a Chicago teaching hospital: implications for antibiotic stewardship. Clin Infect Dis. 49:1175–1184. 20. Engemann JJ, Carmeli Y, Cosgrove SE, Fowler VG, Bronstein MZ, Trivette SL, Briggs JP, Sexton DJ, Kaye KS. 2003. Adverse clinical and economic outcomes attributable to methicillin resistance among patients with Staphylococcus aureus surgical site infection. Clin Infect Dis. 36:592-598. 21. Mossialos E, Morel C, Edwards S, Berenson J, Gemmill-Toyama M, Brogan D. 2009. Policies and incentives for promoting innovation in antibiotic research. (The London School of Economics and Political Science; http://www.lse.ac.uk/LSEHealthAndSocialCare/impacts/Antibiotics%20Report.aspx).

Eight more ways to deal with antibiotic resistance.

The fight against antibiotic resistance must be strengthened. We propose actions that U.S. government agencies and private sector entities can take to...
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