BAD BUGS, NO DRUGS 2002–2020: PROGRESS, CHALLENGES, AND CALL TO ACTION

Abstract

Antimicrobial resistance (AMR) requires a multifaceted response via a One Health approach. Antibiotics make procedures including joint replacement, transplantation, cancer chemotherapy, and premature newborn care possible. The U.S. Centers for Disease Control and Prevention (CDC) estimates that 2 million Americans are infected and >35,900 die from AMR, costing over $20 billion/year. Projections are that this will increase to 350 million cumulative AMR deaths by 2050. In its 2004 report entitled “Bad Bugs, No Drugs: As Antibiotic R&D Stagnates, A Public Health Crisis Brews,” the Infectious Diseases Society of America (IDSA) raised alarm and proposed solutions. In the face of decreasing Food and Drug Administration (FDA) approvals and several program failures, scientific collaboration and regulatory innovation led to updated guidance for common, life-threatening infections. The IDSA and others worked to advance policies for discovery and development of drugs for the most resistant infections. Successes include legislation and public-private partnerships that provide push incentives. Need exists for pull incentives; several models are currently being explored.

INTRODUCTION

Top existential threats to human health in 2019 included climate change, overpopulation, and antimicrobial resistance (AMR) (1). The last 20 years have seen a rapid rise in antibiotic resistance fueled by antibiotic overuse in people, animals, and the environment, as well as a dearth of new antibiotic development. This crisis requires a multifaceted, coordinated response that involves a One Health approach. The U.S. response is coordinated via the Combating Antibiotic Resistant Bacterial National Action Plan, which outlines specific goals and targets for responding to the crisis (2).

The magnitude of the AMR crisis is not fully defined. The CDC released an updated threat report in November 2019 which estimated that at least 2.87 million antibiotic-resistant infections occur annually, or one infection is caused by a resistant pathogen every 11 seconds. In terms of mortality, updated CDC estimates show that at least 35,900 people die in the United States every year due to antibiotic-resistant infections, or one person dies every 15 minutes. If deaths related to C. difficile are included, this is the equivalent of one jumbo jet crash every three days (3). The AMR Review published in the United Kingdom estimated in 2014 that at least 700,000 people globally lose their lives every year due to resistant infections (4). This study estimated that if we do nothing, by 2050, 10 million people will die due to AMR annually worldwide, which surpasses cancer deaths. The CDC also estimates that antibiotic-resistant infections result in $20 billion in excess health care costs annually, due in large part to longer hospital stays for patients whose infections are not easily treated (5). Global estimates point to over 10 million deaths annually due to AMR by the year 2050 if nothing changes (4).

AMR is a life-threatening crisis that impacts patients every day and threatens to undo decades of medical progress. Readily available, safe, effective antibiotics have enabled a host of medical advances, including organ and bone marrow transplantation, cancer chemotherapy, and complex surgeries. These procedures significantly increase patients' risk of infection by weakening their immune systems and/or providing portals of entry for bacteria. Without antibiotic support, none of these therapies are possible. AMR and the lack of new antibiotics jeopardize this progress and place even routine procedures such as joint replacements and obstetric care in jeopardy.

Public awareness about the problem of AMR remains less than optimal (6). Despite a number of efforts to educate and make people aware of the threat of AMR, a vocal and influential patient advocacy group for AMR is lacking. The reasons for this are complex and likely include the fact that so many patients do not survive their infections, the hesitation of health care systems to have their patients with reportable infections discussed publicly, among others.

IDSA'S CALL TO ACTION

The IDSA is a professional society of over 12,000 members, most of whom are physicians caring for patients with infectious diseases. Since 2002, the IDSA has sounded the alarm about AMR and the need to develop new medicines to treat resistant infections. Working on patients' behalf, the IDSA specifically highlighted the rapid decline in development of novel therapies to treat the most resistant bacterial and fungal pathogens. In its “Bad Bugs” policy report, the IDSA proposed legislative, regulatory, and funding solutions to address this increasing public health problem (7). Shortly thereafter, it published an update on the concerning status of the development pipeline as well as a call to action from the medical community (8). Major pharmaceutical companies left the antibiotic space, and most research and development work moved to small biotech companies with limited capacity and budgets. Leaders reported difficulty in securing funding for antibiotic development as the return on investment was low (9,10).

Recognizing that drug-resistant infections can strike anyone—young or old, healthy or sick, the IDSA produced Faces of Antimicrobial Resistance, a series of real life patient stories to highlight the urgent need to combat AMR (11). These compelling and heart-wrenching stories convey a strong sense of urgency for addressing drug-resistant infections and the lack of new antibiotic development.

POLICY, ADVOCACY, AND PROGRESS

Efforts to find solutions have included policy work and advocacy (12). A number of workshops, meetings, and publication efforts have ensued. Key advances include the Generating Antibiotic Incentives Now (GAIN) Act, which was enacted in 2012 as part of the FDA Safety and Innovation Act (SIA). GAIN provided an important first step in supporting antibiotic R&D by granting an additional five years of exclusivity to new antibiotics and antifungals that treat serious or life-threatening infections. The 21st Century Cures Act, enacted in 2016, established the Limited Population Antibacterial Drug (LPAD) pathway, which makes clinical trials more feasible for the most urgently needed new antibiotics. Under LPAD, such antibiotics can be studied in smaller, more rapid clinical trials, which is essential because some of the most highly resistant pathogens are still infecting relatively small numbers of critically ill patients who are challenging to enroll in clinical trials (9,10,13). Paired with these efforts were measures to preserve and optimally use the precious few antibiotics available via antibiotic stewardship programs and to optimize infection prevention and surveillance in humans, animals, and the environment (2,14,15).

Concern about the dwindling antibiotic pipeline led to a call for 10 new, systemically available antibiotics by the year 2020 and further work on clinical trial design and development pathways for drugs designed to treat the most resistant infections. These often have a very narrow spectrum, so the design of special pathogen or narrow spectrum indications became an important focus. Collaboration between academic and government partners, including members of the CDC, the National Institute for Allergy and Infectious Diseases (NIAID), the Department of Defense, the Biomedical Advanced Research and Development Authority (BARDA), and the FDA, led to publication of a white paper focused on developing drugs for resistant pathogens, narrow-spectrum indications, and unmet medical needs (16). This collaboration also led to progress in incentives for antibiotic drug development including push incentives such as the NIH ARLG and public-private partnership CARB-X, both of which have significantly stimulated discovery and early phase development (13).

Progress has been made in the discovery and development of antibiotics, with 13 new systemically available antibiotics becoming available between 2010 and 2019. Indeed, the IDSA's 10 × '20 goal has been achieved. The less positive news, however, is that “nobody's buying” these medicines. The sales of these newly FDA-approved drugs are low; one producer, Achaogen, filed for bankruptcy protection in April 2019, shortly after FDA approval of its new drug. News of this bankruptcy sent a chill through the antibiotic marketplace and further decreased interest in supporting antibiotic research and development. Other companies, including Melinta and Tetraphase, have had to restructure to avoid bankruptcy. Large numbers of antibiotic researchers have been fired in recent years. This trend has accelerated dramatically in the last few months. A rapid “fix” of the broken antibiotic market via pull incentives has been called for (13,17).

The IDSA supports robust, predictable, and understandable incentives that target areas of greatest unmet need and are aligned fully with principles of antibiotic stewardship and appropriate access. Incentives including reimbursement reform and market entry reform seem to have gained the most traction to date. Importantly, both of these “de-link” the incentive from sales of antibiotics and thereby support good stewardship and avoidance of overuse.

In August 2019, the Centers for Medicare & Medicaid Services (CMS) released its final Hospital Inpatient Prospective Payment System (IPPS) rule for FY2020 (18). It includes an increase in the Medicare bundled payment (also known as diagnosis related group or DRG) severity level designation for the diagnosis codes that specify antimicrobial drug resistance, which should result in higher Medicare payments to hospitals for these cases, thus hopefully allowing newer, costlier drugs to be used if necessary (18). In addition, the rule provides for an increase in the New Technology Add on Payment (NTAP) and automatically considers all Qualified Infectious Diseases Product (QIDP) antibiotics as meeting the substantial clinical improvement criterion for an NTAP payment. This makes it easier for antibiotics to qualify for NTAP, but many hospitals still find the administrative burden associated with NTAP too great and do not seek these payments except in cases of very costly drugs or devices (not antibiotics).

The IDSA supports removing reimbursement for new antibiotics out of the DRG and allowing them to be reimbursed separately. This will help ensure that patients who need these drugs can access them and will help stabilize the precarious antibiotic marketplace for developers. The IDSA believes it is essential that reimbursement reform or any other policies aimed at incentivizing antibiotic research and development be paired with robust stewardship policies to guide appropriate antibiotic use and preserve the effectiveness of new antibiotics, thereby preserving our nation's investment in the discovery and development of these new antibiotics. In order to receive higher reimbursement for antibiotics, hospitals must be required to implement stewardship programs that align with CDC recommendations and report antibiotic use and resistance data to the National Healthcare Safety Network.

The bipartisan Developing an Innovative Strategy for Antimicrobial Resistant Microorganisms (DISARM) Act was introduced in the Senate in June 2019 by Senators Johnny Isakson (R, Ga.) and Bob Casey (D, Pa.) and in the House of Representatives in July 2019 by Representatives Danny Davis (D, Ill.) and Kenny Marchant (R, Tex.). This bill would carve new antibiotics that treat serious or life-threatening infections out of the DRG and pay for them separately to boost their reimbursement; require hospitals to establish antibiotic stewardship programs that align with CDC recommendations; and require hospitals to report antibiotic use and resistance data to the CDC National Healthcare Safety Network. The goals of DISARM are to help ensure that patients can access new antibiotics when they are needed, to stabilize the antibiotics market for developers, and to ensure that these precious resources are used in the best way possible.

While reimbursement reform and the proposed DISARM Act are encouraging first steps, salvaging the antibiotic research and development infrastructure will require more effort. Long-term solutions such as Market Entry Rewards are gaining traction but need further work in order to be realized.

Finally, all physicians need to be a voice for patients. They must speak for their patients, tell their stories, and urge action. They should advocate for prompt publishing of data and updating of guidelines and for availability of new drugs in their hospitals. Most of all, physicians must reach out to legislators in support of DISARM (https://www.idsociety.org/ActOnDISARM) and get their colleagues involved. AMR affects everyone and threatens all medical care. An AMR movement is essential!

DISCUSSION

Due to technical problems with the Grand Hotel audiovisual equipment, the questions by Drs. Selker, Dupont, Simari, and Coller associated with this paper and the responses by Dr. Boucher could not be transcribed.