February 17, 2015
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AAAS 2015: Keeping up with antibiotic resistance

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Antibiotics play a pivotal role in the treatment of bacterial infections, and they are an essential and lifesaving aspect of modern medicine. The reality of antibiotic resistance, in which strains of bacteria adapt to and survive the action of antibiotics, however, is becoming increasingly problematic.

The consequences of antibiotic resistance are most keenly felt in low- and middle-income nations, where antibiotic-resistant strains of infections like pneumonia, have led to a growing number of fatalities.

In a news briefing titled “Antibiotic Resistance: An Environmental Problem Threatening Global Health Care,” speakers at the 2015 American Association for the Advancement of Science (AAAS) meeting in San Jose, California, discussed the importance of antibiotics and the ongoing challenge of antibiotic resistance.

“Antibiotics are arguably the single-most important class of drug in human medicine. In the 70-odd years they have been in use, they have saved countless lives, reduced human suffering and greatly improved the chances of surviving surgical procedures,” Diarmaid Hughes, PhD, professor of medical molecular bacteriology at Uppsala University, Sweden, said. “Currently, we are at risk of losing the effectiveness of antibiotics because resistant bacteria are becoming more prevalent in both the hospital and community environments.”

Diarmaid Hughes

A global problem

In her presentation, Anna Zorzet, PhD, of ReAct (Action on Antibiotic Resistance), cited alarming data on the toll of worldwide antibiotic resistance. For example, antibiotic resistance has resulted in more than 38,000 deaths in Thailand, and has incurred direct societal costs of about $140 million and more than $1.3 billion in indirect costs. In the United States, antibiotic resistance has led to 23,000 deaths, approximately $20 billion in direct societal costs, and more than $1.3 billion in indirect costs.

In Europe, 25,000 deaths have been attributed to antibiotic resistance, leading to approximately $1.5 billion in societal costs.

Anna Zorzet

Zorzet also discussed the role of the environment in antibiotic resistance, noting that bacteria in any environment may become resistant through specific genetic changes or by picking up antibiotic resistance mechanisms from nearby bacteria.

“In the presence of an antibiotic, resistant bacteria are better off than nonresistant ones and can increase in prevalence,” she said in her presentation. “Today, resistance to different antibiotics as well as heavy metals like copper and silver are commonly found together on genetic elements that can easily spread between bacteria. This means that bacteria can become resistant to multiple antibiotics at once. One of these antibiotics is then enough to select for, and thus maintain, all other [antibiotic resistance] mechanisms.”

Zorzet said these mechanisms predated the use of antibiotics by many years and could be found in environmental bacteria and as protective measures in antibiotic-producing microbes. However, they were not commonly found in pathogenic bacteria. The existence of antibiotic resistance in pathogenic bacteria has been largely a recent phenomenon, she said.

“During the 70 or so years that humans have used antibiotics, antibiotic resistance has become prevalent in pathogenic and environmental bacteria alike,” Zorzet said. “All resistance genes in the environment can be regarded as a big “pool” of resistance genes that can potentially transfer to pathogenic bacteria.”

Along with the threat of antibiotic resistance, Zorzet said, is the emergence of new multidrug-resistant (MDR) bacteria. She cited the example of “swine MRSA,” which has infected swine farmers in Denmark and their families. An investigation of the origin of the bacterial strain responsible for this disease suggests that it originally spread from humans to pigs, and subsequently gained resistance in the antibiotic-rich environment of swine farming. As a result, this resistant but less virulent MRSA is occurring in humans.

Zorzet said recent evidence shows that environmental contamination with antibiotics plays a significant role in the emergence and spread of MDR bacteria. “Waste from large-scale animal farms, use in aquaculture and wastewater from antibiotic manufacturing, hospitals and municipalities are major sources of [antibiotic resistant] genes and antibiotic pollution in the environment,” she said.

Zorzet cited a study of antibiotic resistant genes at three Chinese swine farms, which found increased levels of antibiotics in manure and soil, and three times as many unique antibiotic resistant genes vs. control manure and soil.

“As antibiotics are transported with water and through the sediments and soil, gradients of different antibiotic concentrations will form,” she said. “Even very low antibiotic concentrations may be enough to select for highly resistant bacteria.”

Moreover, activities like travel and international commerce facilitate their global spread. “International travelers are, for example, often colonized with resistant bacteria upon their return home,” Zorzet said. “[New Delhi metallo-beta-lactamase–producing Klebsiella], that originated in India but is now a major problem in all corners of the world, is a striking example.”

The mechanism of selection

In his presentation, Hughes discussed the need to develop new antibiotics for which there is no resistance.

“This process will be both expensive and technically challenging, but considering the medical dangers associated with not having antibiotics, it is likely that sufficient resources will eventually be spent to ensure success,” he said. “However, the danger is that if we continue to ‘do business as usual,’ we will quickly select resistance to these previous new antibiotics.”

He said the disruption of the current pattern will require balancing antibiotic use for the best clinical outcome with unintended selection for resistance. Additionally, improved knowledge is needed of the origins, mechanisms and selection of antibiotic resistance.

“One view — that resistance is selected in patients undergoing antibiotic therapy, where bacteria are exposed to very high drug concentrations — implies that improved control of patient therapy might be the most effective way to control resistance emergence and spread,” Hughes said. “However, another view, for which until recently there was no experimental evidence, is that resistance might be selected at the low concentrations found in the wider environment. We have now shown experimentally that very low levels of antibiotics do in fact select and enrich for resistant bacteria.”

This suggests that a significant amount of the selection and enrichment for antibiotics may not be occurring in health care settings, according to Hughes.

“This influences how we should think about optimal strategies and approaches to restrict resistance development against any new antibiotics that might be introduced into medicine in the future,” he said. “We may need to focus more resources on restricting the release of active compounds into the environment; for example, from pharmaceutical production plants, from farming activities, from hospitals and from water and sewage treatment plants, so as to restrict the selection of antibiotic resistance caused by low level exposure to drugs of the global bacterial population.”

In addition, Hughes said low levels of antibiotics tend to select for resistant bacteria that have a high biological fitness, indicating that the bacteria will likely survive in the environment despite subsequent restrictions on the antibiotics. He cited recent evidence showing that low levels of different antibiotics act together to select MDR bacteria.

“Thus, the cumulative concentration of different environmental chemicals selects and enriches antibiotic-resistant bacterial populations,” he said.

References:

Hughes D. Selection of resistance by very low levels of antibiotics. Presented at: AAAS Annual Meeting; Feb. 12-16, 2015; San Jose, California.

Wright G.Resistance-guided antibiotic discovery. Presented at: AAAS Annual Meeting; Feb. 12-16, 2015; San Jose, California.

Zorzet A. Global importance of antibiotics and consequences of antibiotic overuse — the role of the environment. Presented at: AAAS Annual Meeting; Feb. 12-16, 2015; San Jose, California.

Disclosures: Hughes, Wright and Zorzet report no relevant financial disclosures.