Running on empty? U.S. nears 'painful' transition to antibiotic conservation
IOM panel cites antibiotic misuse in hospitals, communities, farming
After decades of consuming antibiotics like "cheap petroleum," the United States may be nearing the equivalent of an antimicrobial energy crisis, when rationing and higher prices curb demand for the few remaining effective agents, warns the Institute of Medicine (IOM) in Washington DC.
In much the same manner as it sounded the alarm on the emerging infections issue in 1992, the IOM recently issued a sweeping report on antibiotic resistance that outlines the critical issues and options related to preserving antibiotic efficacy.1 The IOM is a nonprofit group that provides health policy advice to the federal government through its congressional charter under the National Academy of Sciences. The report was issued by the IOM Forum on Emerging Infections, which includes members from medical academia and industry as well as ex officio government representatives.
Annual costs due to drug-resistant infections run into the billions of dollars in the United States when hospitalizations, lost workdays, and deaths are factored in, the IOM report noted. It calls for increasing national and global surveillance for resistant infections and identifies patterns of antibiotic misuse and overuse in hospitals, communities, and agriculture. It is estimated, for example, that 25% to 45% of the antibiotics administered in hospitals are clinically unnecessary. (See related stories, pp. 99, 100.)
Among the regulatory options cited in the report is giving the Centers for Disease Control and Prevention authority to go beyond voluntary guidelines and "enforce legal duties regarding [antibiotic] resistance." Those might include, for example, requiring states to report data on antibiotic resistance in their disease-reporting systems to the CDC. The current system is essentially voluntary and far from uniform, the IOM noted. The report also discusses options for removing market disincentives for new drug development, and weighs the pros and cons of restricting antibiotics to preserve efficacy. Such strategies, however, open up complex legal and ethical questions, including the right of infected patients to receive therapy vs. the public health need to curtail overall antibiotic use to reduce resistance, the IOM noted.
"The initial [antibiotic] treasure trove, however, is all but exhausted," the IOM report concludes. "Yet, like cheap petroleum, the habit interferes conceptually and practically in market-incentive structures with the development of successors, and there is high risk that what remains of the treasure will be wasted by its imprudent use. The transition period as the market makes the necessary adjustments will be painful, and it is possible to imagine a scenario in which antibiotics with lower therapeutic indexes at thousands of dollars per course of treatment could instill a need for rationing and special development incentives, to great consumer distress, particularly in populations whose financial resources are constrained."
Since the introduction of penicillin more than 50 years ago, the world has become accustomed to the availability of antibiotics that are promptly and reliably effective, relatively free of side effects, and inexpensive compared to other medical and surgical interventions, the IOM emphasized in the report. Though the first signs of antibiotic resistance appeared as early as 1945, only in the last decade has it become clear that "almost every infecting species was developing resistance to our common antibiotics, and that we [are] beginning to run out of the repertoire of agents that could be used to deal with infection," said the chairman of the IOM forum, Joshua Lederberg, PhD, Nobel laureate and Sackler Foundation Scholar at Rockefeller University in New York City.
"Most alarming, as indicated in our report, are penicillin-resistant pneumonia [and] vancomycin-resistant cocci," he said. "Vancomycin is the drug of last resort; the one usable after all the others have been exhausted in treating a variety of coccal infections. And the situation has begun to appear on the verge of desperation. [That] means going back to the days before antibiotics were available, when any peritonitis was almost a signal of looming death, when wound infections were a severe limitation on what one could do with surgery, when ordinary childhood infections would be quite serious. That's the challenge we are facing."
Joining several other IOM committee members at a May 14 press conference to release the report, Lederberg returned to the energy conservation metaphor.
"We face a situation similar to what we have with respect to our energy supply, where the cheap oil that we have at the moment is very frustrating in terms of putting systems in place for energy conservation, alternative [fuel] sources and so forth," he said. "We have had a generation of very cheap antibiotics, which are used promiscuously, which are still capable of doing a good deal of benefit, but which I think are in the process of continuing to be wasted."
New generations of antibiotics can be produced, but they will be expensive, he added, asking "figuratively" if there might be some benefit in taxing the existing cheap antibiotics to constrain their use and provide a new source of funding for drug development.
"[That would] provide another incentive to limit their use to those circumstances to where they are really going to do some good," he said.
New drugs, diagnostic breakthroughs
Indeed, there is evidence that antibiotic resistance can be reversed or mitigated by reductions in antibiotic use, the IOM reported, citing the need to find "innovative ways of accomplishing such reversal . . . by restoring susceptible flora and thus extending the useful life of existing antibiotics." In addition, microbiological research and new drug and vaccine initiatives are adding new weapons to the fray. (See Abstract and Commentary, p. 110.)
"The genomes of microorganisms are being sequenced," added Renu Gupta, MD, IOM panel member and senior medical director for infectious diseases at Bristol-Meyers Squibb in Princeton, NJ. "As the functions of specific genes are understood, the industry will be better positioned to come up with drugs that will target specific bugs."
Likewise, such research may lead to rapid tests that would help clinicians quickly determine drug susceptibility patterns and delineate between bacterial infections warranting therapy and viral infections that should not be treated with antibiotics.
"It is has been estimated that up to 40% of the antibiotics prescribed for respiratory infections are inappropriately prescribed," noted Gail Cassell, PhD, IOM panel member and vice president for infectious disease research at Eli Lilly in Indianapolis. "Part of this is associated with our inability right now to provide an accurate rapid diagnosis to distinguish between viral and bacterial respiratory pathogens."
While microbiological research holds promise for solving such problems, a greater knowledge of behavioral science is also needed to understand and curb inappropriate antibiotic use. The IOM described antibiotic resistance as a multifactorial problem fueled by diverse contributing factors like patient anxiety; physician fear of litigation; unscrupulous advertising by drug companies; and cost-saving efforts under managed care.
"There has been well-founded concern [regarding managed care] that in the haste to conserve physician time and patient visits that there might be motives to overprescribe antibiotics," Lederberg said, adding that this approach may be seen as "the most time-effective way of disposing of a patient that comes in the office door, rather than devoting the time needed for careful diagnostics and determination of which agent ought to be used."
Endorsing previous recommendations by the American Society for Microbiology (ASM) for a national surveillance system, the IOM noted that even current dire projections are probably based on underestimates of the extent of antimicrobial resistance. The ASM recommended the national surveillance system be funded by a variety of sources, including federal and state governments, industry, and academic institutions. Likewise, risk-benefit research is urgently needed to reassess the massive amounts of antibiotics used in agriculture, but the U.S. Department of Agriculture has an insufficient budget to take on the project, Cassell noted.
"The most critical thing that we could hope would happen as a result of this is that appropriate funding be put in place at the CDC, the FDA, and the USDA so we can have in place a meaningful surveillance system," she said.
Currently, antimicrobial resistance surveillance is fragmented among a variety of national and international systems, said James Hughes, MD, assistant surgeon general and director of the CDC national center for infectious diseases. Upgrading and integrating such systems could assist clinicians in making decisions about treatment of patients and help the industry set priorities for new drug development, noted Hughes, an ex officio member of the IOM panel.
"For antimicrobial resistance [surveillance] you need microbiologic data from the clinical and public health laboratories, epidemiologic data on the patient, information on outcomes of illness caused by drug-resistant organisms, which are often missing from existing surveillance systems," he said.
Indeed, the IOM notes in the report that hospital laboratories, though a major source of surveillance data, have numerous limitations. In addition, hospitals are increasingly outsourcing testing to cut costs, raising issues of laboratory quality control.
"Not all organisms are monitored and tested for resistance," the report states. "For example, despite its intrinsic importance and the considerable media coverage of vancomycin resistance, many U.S. hospital-based laboratories continue to exclude from testing enterococcus isolates from urine and wound cultures, so that unknown numbers of vancomycin-resistant isolates are simply never recognized in these systems."
In addition, hospital restructuring trends have resulted in a decrease in total patient occupancy days and an expansion in the number of intensive care beds. With hospitals essentially becoming large ICUs and antibiotic administration increasing accordingly, at least six nosocomial pathogens are now multidrug-resistant: Actineobacter, Enterobacter, Klebsiellae, Pseudomonas, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant enterococci.
"Drug resistance of these pathogens is now more common in ICUs than in inpatient wards, and more common in inpatient wards than in the corresponding outpatient settings," the IOM reports. "It is hard to resist the conclusion that this correlates with the fact that, in general, patients in ICUs receive an antibiotic on about 70% of ICU days. For inpatient wards, the figure is around 40%. These changes are not confined to the most vulnerable populations within hospital walls. As the resistant pathogens increase in number and the antibiotic armamentarium shrinks, transmission to the larger population will also increase and, in many cases, become a problem for the general public."
Complicating the picture - and underscoring the need for global cooperation - is how resistance patterns can vary widely both nationally and internationally in hospitals, communities, and farms. While international surveillance links should be strengthened, the IOM also suggested working with the World Health Organization in Geneva to curb the unrestricted availability of antibiotics in some countries.
"In many countries they are sold over the counter [rather than] administered by trained physicians, which certainly creates large problems in terms of leading to selective pressure and ultimately antibiotic resistance," Cassell said.
Such international concerns have also been cited in discussions of emerging infections and influenza pandemics, and antibiotic resistance could worsen the impact of such events.
"We cannot afford to ignore resistance problems in far-away places because of the speed of international travel and the movement of food and food products around the world," Hughes said. "Just imagine when the next influenza pandemic does occur, we are going to see complications caused by drug-resistant bacterial strains that will be causing secondary bacterial pneumonias in patients with influenza."
Reference
1. Institute of Medicine. Antimicrobial Resistance: Issues and Options. Washington, DC: National Academy Press; 1998.
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