By David Longtin and Henry I. Miller
It was not until the years just after World War II when streptomycin, the first truly broad-spectrum antibacterial agent, came onto the market, and penicillin began to be widely available that the Golden Age of antibiotic therapy really began. Before that, even seemingly trivial infections of the skin, lungs or other organs could lead to sepsis and death. We may now be on the verge of returning to a pre-antibiotic era, a prospect that public health experts find terrifying.
Bacteria are champions of Darwinian selection: As we try to kill them with antibiotics, they mutate in myriad ways in order to survive. And they have quite a repertoire: Among other tricks, they develop less permeable walls to keep the antibiotics out, create ways to degrade or extrude them or alter the intracellular targets so that the antibiotics no longer work on them. Bacteria can even transfer these evolutionary adaptations from one species to another, making it ever more imperative for us to come up with new antibiotics that work through novel mechanisms. It’s a never-ending escalating arms race, and the harsh reality is that the bacteria are winning it.
Increasingly, microorganisms are developing resistance not only to single antimicrobial agents, but to several. These latter organisms are called multidrug-resistant, or MDR, strains. In some cases, the microorganisms have become so resistant that no available antibiotics are effective against them. This led Dr. Arjun Srinivasan, assistant director of the Centers for Disease Control and Prevention (CDC), to paint this dire picture last year:
We are quickly running out of therapies to treat some of these infections that previously had been eminently treatable. There are bacteria that we encounter, particularly in health-care settings, that are resistant to nearly all — or, in some cases, all — the antibiotics that we have available to us, and we are thus entering an era that people have talked about for a long time. . . We’re in the post-antibiotic era. There are patients for whom we have no therapy, and we are literally in a position of having a patient in a bed who has an infection, something that five years ago even we could have treated, but now we can’t.
According to the CDC, in 2011 there were approximately three quarters of a million hospital-acquired infections in U.S acute care hospitals, and about 75,000 patients died during their hospitalizations. This daunting tally excludes people who acquire infections in other health-care settings, such as outpatient surgery centers, where more than 60% of all operations are now performed, and long-term care facilities. As pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) have moved beyond health-care facilities, drug-resistant infections have become common in the community at large.
Drug resistance has important implications. People infected with drug-resistant organisms are more likely to have longer and more expensive hospital stays and are more likely to die as a result of the infection. When the first-line drug of choice for treating an infection won’t work, physicians must resort to second- or third-choice drugs that may be less effective and more toxic.
At the same time that bacterial resistance to antibiotics is increasing, the number of drug and biotech companies developing new antibacterials is shrinking. This decline is due to a number of factors, including lack of industry productivity, the low return on investment of antibacterials compared with other therapeutics, difficulty in identifying new compounds with traditional discovery methods, regulatory requirements that require large and complex clinical trials for approval, and initiatives that encourage antibiotics to be used as sparingly as possible (to minimize the spread of resistance).
Neither the federal government nor private scientific philanthropy is adequately supporting research on antibiotics and antibiotic resistance. The National Institutes of Health’s National Institute of Allergy and Infectious Diseases is “funding and conducting research on many aspects of antimicrobial (drug) resistance, including basic research on how microbes develop resistance, new and faster diagnostics, and clinical trials designed to find new vaccines and treatments effective against drug-resistant microbes.” And another agency within the U.S. Department of Health and Human Services, the Biomedical Advanced Research and Development Authority (BARDA), funds antibiotics R&D, including costly late-stage (Phase III) clinical trials, at some of the few pharmaceutical companies still in the field. Since 2010, BARDA has partnered with six drug makers and has sponsored nine molecular candidates in Phase II/III clinical trials to test the drugs’ efficacy against biothreats (e.g., plague) and some of the worst bacterial pathogens now threatening society.
A 2002 change in FDA requirements for the clinical testing of antibiotics helped to create the shortage of new antibiotics. To enhance the statistical power – and therefore, the confidence level — of Phase III antibiotic clinical trials, FDA more than doubled the number of patients required. As antibiotics researchers David Shlaes and Robert Moellering observed in that same year, because in the pharmaceutical industry business considerations play a critical part in setting R&D priorities, corporate
programs with modest potential markets and large costs are automatically deprioritized unless there is some other, overriding strategic issue to be considered. Thus, one unintended result of promulgating these guidelines will be a decrease in the number of companies performing antibacterial research.
Their prediction was accurate: Since 2002 all but a handful of the major pharmaceutical companies have abandoned their antibiotics R&D programs.
From 2009 to 2012, in part at the urging of members of Congress who had strong opinions but little understanding of the clinical testing of antibiotics, FDA’s policy toward antibiotics testing became so risk-averse and punitive that clinical trials of new antibiotics virtually ground to a halt. FDA even proposed that patients enrolled in clinical trials for hospital-acquired pneumonia would be ineligible if they had received another antibiotic within 30 days prior to their participation, making such studies virtually impossible to conduct in the United States.
In July 2013, however, the FDA released new draft guidelines for the conduct of antibiotic clinical trials – part of a self-described “reboot” of policy at the agency. The new guidelines may help, but some experts, such as UCLA Professor of Medicine Brad Spellberg, have warned that the new guidelines don’t represent significant change, and that much more improvement is needed for trials to become feasible again.
FDA should adopt a promising concept originally proposed by the Infectious Diseases Society of America (IDSA) known as the Limited Population Antibacterial Development (LPAD) pathway, via which “a drug’s safety and effectiveness would be studied in substantially smaller, more rapid, and less expensive clinical trials” — similar to the way “orphan drugs” are developed for rare diseases. Once approved, LPAD-type products would be labeled for use in small, well-defined populations of patients for whom the drugs’ benefits had been shown to outweigh their risks. In this model, studies of potential new antibiotics would need to enroll hundreds of patients instead of the thousands now required and could be carried out relatively quickly.
However, as Shlaes and Moellering have pointed out, to revive antibiotic R&D, along with regulatory reform we will also need “value-based” pricing, so that return on investment from antibiotic development is comparable to that of other drug classes.
Consequently, we should expect LPAD-style antibiotics to cost as much as $20,000-30,000 per course. This is not unreasonable, given that many marginally effective cancer drugs cost many times that amount; a new two-drug regimen, sofosbuvir and ribavirin to treat Hepatitis C, is about $84,000 wholesale; and Truvada, the drug combination of emtricitabine and tenovir for HIV prophylaxis, costs $15,000 per year. In 2010, Forbes compiled a list of nine little-used drugs whose cost for the average patient exceeded $200,000 per year.
One proposed legislative fix for the market failure in antibiotics development is the bipartisan “Developing an Innovative Strategy for Antimicrobial Resistant Microorganisms (DISARM) Act of 2014,” which would require the Centers for Medicare and Medicaid Services (CMS) to reimburse significantly more for LPAD-like antibiotics. Currently, hospitals may actually lose money because reimbursements fail to cover the cost of the drugs. (Hospitals would not be encouraged to over-use the drugs, however, because reimbursement would cover only their cost, but no profit-margin.)
Another possible stimulus to R&D on antibiotics derives from a 2007 law — a transferable “priority review voucher” awarded by FDA upon approval of a new drug for a neglected tropical disease. This PRV would entitle the drug developer to move a new product of its choice to the head of the FDA review queue, or it could be sold to another company. The company that ultimately redeems the voucher with the FDA could cut months from the review time of a New Drug Application, which could be worth hundreds of millions of dollars to a company eager to begin marketing a potential blockbuster. This voucher program should be expanded to include drugs for any infection.
Another incentive to encourage companies to undertake antibiotics R&D was recommended in a 2009 analysis from the London School of Economics: a guaranteed government purchase of a defined supply of the antibiotic that would go into a national stockpile. A precedent for this is drugs developed for pandemic influenza and anthrax.
With more enlightened regulation and improved return on investment, which are necessary to make antibiotic development attractive, perhaps we can avoid the extinction of the antibiotic era – and the reversal of our species’ increasing longevity. Perhaps.
David Longtin is a Washington DC-based biomedical writer. Henry I. Miller is a physician and molecular biologist; he was the founding director of the FDA’s Office of Biotechnology and is currently the Robert Wesson Fellow in Scientific Philosophy and Public Policy at Stanford University’s Hoover Institution.