Live and let live: Why trying to ‘kill the bug’ only spurs more antibiotic resistance

Live and let live: Why trying to kill the bug’ only spurs more antibiotic resistance

CDC: C. diff and CRE are urgent’ threats

By Gary Evans, Executive Editor

Antibiotics have saved many a life, but the resilient, resistant microbe remains — rendering another drug useless against a spreading infection. As counterintuitive as it sounds, there may be another way. An intriguing path forward is emerging in a new "damage response" paradigm that seeks less to eradicate pathogens than to mitigate their adverse effects, Brad Spellberg, MD, said recently in San Francisco at IDWeek 2013.

"Maybe we should stop focusing on killing the bug," said Spellberg, a past president of the Infectious Diseases Society of America (IDSA) and author of The Rising Plague.¹

Indeed, the whole image of a "battle" between the bugs and the drugs may be an analogy that is about as exhausted as the concept itself.

"We need to stop viewing our relationship with microbes as a war," Spellberg said at the closing plenary at IDWeek, which drew some 6,500 infectious disease clinicians. "Killing is only going to get us so far. The ideal goal is to achieve peaceful coexistence."

An infectious disease physician at Harbor-UCLA Medical Center in Los Angeles, Spellberg was less conciliatory toward an agricultural industry that fuels bacterial resistance by using tons of growth-promoting antibiotics in farm animals.

"Of course we need to get antibiotics out of animal feed — this is a national disgrace," he said.

Of some 15.5 million kg of antibiotics consumed annually in the United States, about 80% are administered to animals, he noted. Moreover, 8.5 million kg of the antibiotics used in farm animals are similar or identical to human drugs. Misuse and overuse of antibiotics is widespread in health care as well. As it currently stands, about half of all the antibiotics used in health care are unnecessary, thus the increasing calls for drug stewardship programs with regulatory teeth. (See related story, p. 125.)

Continuing to expose the environment to mass quantities of antibiotics creates selective pressure to kill off susceptible microbes in favor of those naturally resistant to the drugs being used. And it’s not like the diverse dominion of bacteria need any help. Consider their overwhelming advantage expressed in sheer numbers.

"We are never going to defeat organisms that outnumber us by a factor of 1022, outweigh us by a 100-million fold, can replicate 500,000 times faster than we can, and have been doing this for 10,000 times longer than our species has existed," he said.

Spellberg is not a defeatist, but he can read the writing on the cave wall — microbes have ruled the earth for millennia while the antibiotic era is less than a century old. Indeed, he noted in a paper published earlier this year that microbes found in ancient underground caves were naturally resistant to antibiotics they could not have possibly been exposed to — synthetic drugs developed in the 20th century. "These results underscore a critical reality: antibiotic resistance already exists, widely disseminated in nature, to drugs we have not yet invented," he noted.2

Thus antibiotic resistance is the predictable outcome of drug development, which in turn drives the need for new drugs. This is not a surprise, but evidence of the maxim that "every system is perfectly designed to produce the results it gets," he explained.

"The future is actually pretty easy to predict," Spellberg said. "There are three things guaranteed in life: death, taxes and resistance. We are already admitting patients with community-onset ESBL (extended spectrum β-lactamase producing Enterobacteriaceae). They are increasing in frequency before our eyes. That will continue, which will result in a continued increase in carbapenem use, which will drive continued increases in carbapenem resistance and pan resistance, which ultimately — if we do not develop new counter measures — is going to escape the hospital and start circulating in communities."

The century-old dogma

Yet the primary medical approach remains "kill the bug," a paradigm Spellberg traced back to a 1913 landmark paper that advised using chemicals to eradicate harmful microbes.3

"Our fixation, our fascination with killing the bug really dates back a 100 years," he said. "But the intellectual framework to challenge this dogma has been around now for a decade and it is called the damage response framework.⁴A tenet of this framework is that host damage which we perceive as clinical disease can be caused by host factors, microbial factors or both. And if this is true then that means you should be able to treat disease by treating the host or by treating the interaction between host and microbe so that disease does not ensue."

Given the historical inevitability that antibiotics will always select out resistant strains, Spellberg and other self-described "renegades" in infectious diseases are arguing that it is time to consider alternative approaches that include altering hostmicrobe interactions in order to modify disease without directly attacking microbes.

In addition to implementing widespread antibiotic stewardship measures to preserve the fading efficacy of current drugs, Spellberg urges investment in a promising line of research that suggests bacteria can be "disarmed," rendered benign without using an eradication approach. For example, Spellberg and colleagues found that a novel class of antibiotics called LpxC inhibitors — which block synthesis of gram-negative endotoxins that trigger the human immune response — did not kill Acinetobacter baumannii but did prevent it from causing disease in mice.Staphylococcus aureus and Candida, the respective second and third most common causes of bloodstream infections.

Over-reliant on hand washing?

While such strategies await clinical validation, infection preventionists must hold the line against transmission of antibiotic-resistant pathogens through measures such as patient isolation and environmental disinfection. Spellberg took a systems view of the problem, saying current infection control approaches rely too much on something that has historically been practiced at a high rate of unreliability: hand hygiene.

"The cornerstone of infection prevention has been and will remain hand washing — we know this," he said. "But from a system perspective, from a policy perspective, relying upon something that requires sustaining changes in human behavior is risky. We are never going to get perfection — humans are imperfect beings."

Available technology should be brought to bear on the problem so that "if we are not perfectly compliant, disaster does not ensue," he said.

"We have had self-cleaning ovens for three decades. Why don’t we have self-cleaning hospital rooms? The patient is discharged, you close the door, press a button and zap the entire room with disinfectant far more adequately that it is done now," Spellberg said. "These kinds of technologies exist. We need to optimize them and conduct some comparative effectiveness research, push them into the clinic, and ensure that payers will pay for them."

Similarly, technology can provide an answer to the common problem of physicians prescribing antibiotics for infections of viral origin, which Spellberg attributes to a very primal emotion.

"It’s fear of being wrong, fear of the unknown — of not being able to truly distinguish bacterial from viral infections with the patient sitting in front of you at the moment," he said. "The way to deal with that fear is rapid diagnostics — we need technology to bolster this. The technology exists. We need to help get it translated and pushed into the clinic, and make sure that payers will reimburse for its use."

"With these kinds of [approaches], at least resistance will emerge more slowly because you are not directly trying to kill the bug," he added.

CRE threat, 10-year projected increase

Resistance is emerging anything but slowly now, moving out into a wide variety of pathogens that cause more than 2 million infections a year and 23,000 deaths in the United States, according to a recent report by the Centers for Disease Control and Prevention.6 Many more die from other conditions that were complicated by an antibiotic-resistant infection. In most cases, antibiotic-resistant infections require costlier treatments, extend hospital stays, necessitate additional doctor visits and healthcare use, and result in greater disability and death compared with infections that are easily treatable with antibiotics, the CDC reported. Estimates of the total economic cost of antibiotic resistance have ranged as high as $20 billion annually in excess direct healthcare costs, with additional costs to society for lost productivity as high as $35 billion a year, the CDC reported. While that sounds like a formidable enough problem, the prevalence of drug-resistant pathogens is almost certainly greater than that captured and extrapolated from the limited surveillance systems.

For the first time, the CDC categorized the major drug-resistant microorganisms into threat categories of "concerning," "serious" and "urgent." While the aforementioned ESBL was labeled a serious threat in the CDC report, two other health care associated infections (HAIs) were given the highest threat ranking of urgent: Clostridium difficile and carbapenem resistant Enterobacteriaceae (CRE). An estimated 140,000 healthcare-associated Enterobacteriaceae infections occur in the United States each year; about 9,300 of these are caused by CRE.

"Up to half of all bloodstream infections caused by CRE result in death. Fortunately, bloodstream infections account for a minority of all healthcare-associated infections caused by Enterobacteriaceae," the CDC report stated. "Each year, approximately 600 deaths result from infections caused by the two most common types of CRE, carbapenem-resistant Klebsiella spp. and carbapenem-resistant E. coli."

How big of a potential threat does the CDC consider CRE? One indicator is that it receives a higher threat rating than MRSA, which kills more than 11,000 patients annually. However, invasive MRSA infections have declined the last few years and there are still some drug treatment options. The same can’t be said for CRE, some strains of which emerged dramatically out of Asia only a few years ago and now threaten to spread widely in the U.S. health care system.

"CDC laboratories have confirmed at least one type of CRE in healthcare facilities in 44 states," the report states. "About 4% of U.S. short-stay hospitals had at least one patient with a serious CRE infection during the first half of 2012. About 18% of long-term acute care hospitals had one."

The CDC is clearly concerned that CRE is going to continue to increase, as one of the factors used in designating threat status in the report is a "10-year projection of incidence."

C. diff reservoirs poorly understood

The other urgent HAI is C. diff, which has dramatically increased over the last decade with the emergence of the NAP1 virulent strain. The strain is resistant to florquinolones, which are commonly used to treat many other hospital infections, but there are still other drug therapies available. The bigger problem is that antibiotic use in general predisposes patients to acquire C. diff, which can emerge after the commensal bacteria in the gut have been wiped out by treatment for other infections. Some 250,000 people are hospitalized annually for C. diff, with 14,000 patients dying as a result.

The routes of C. diff transmission are poorly understood, as a recent genome study found that more than half of hospitalized cases did not acquire the organism from another patient a finding that raises major questions about the current infection control approach for C. diff.⁷(See related story.)

"This is a very intriguing study where they looked at applying whole genome sequence to C. diff," said Victoria Fraser, MD, co-director in infectious diseases at Washington University School of Medicine in St. Louis, MO. "They typed [strains] and did whole genome sequencing and they found some interesting results that were unexpected. People have assumed that the vast majority of C. diff transmission comes from hospitals and goes out into the community. But what they identified really were dramatically [different] groups of acquisition, many of which could not be linked to another case — could not be linked to the hospital."

Delivering the Maxwell Finland Lecture at IDWeek, Fraser said the study underscores that "we don’t completely understand the reservoir or the transmission for C. diff in and out of the hospital, the role of agriculture, the role of food as well. If we are going to make headway I think we are going to have to think more globally about transmission dynamics. There have been great improvements in reductions of HAIs — [particularly] CLABSIs, ventilator associated pneumonia and MRSA — but we are really failing to control antibiotic resistance organisms."

References

1. Spellberg, B. (2009) Rising Plague: The Global Threat from Deadly Bacteria and Our Dwindling Arsenal to Fight Them. Amherst, NY: Prometheus Books.
2. Spellberg B, Bartlett JG, Gilbert DN. The Future of Antibiotics and Resistance N Engl J Med 2013;368:299-302
3. Ehrlich, P. Chemotherapeutics: Scientific Principles, Methods, and Results. Lancet Aug. 13, 1913
4. Casadevall A, Pirofski LA. The damage-response framework of microbial pathogenesis. Nat Rev Microbiol 2003;1:17-24
5. Lin L, Tan B, Pantapalangkoor P, et al. Inhibition of LpxC protects mice from resistant Acinetobacter baumannii by modulating inflammation and enhancing phagocytosis. MBio 2012;3:pii:e00312-12
6. Centers for Disease Control and Prevention. Antibiotic Resistance Threats in the United States, 2013: http://1.usa.gov/15yIo29
7. Eyre DW, Cule ML, Wilson DJ, et al. Diverse sources of C. difficile infection identified on whole-genome sequencing. N Engl J Med 2013;369:1195-1205