By P.J. Heller
Treating multidrug-resistant organisms with antibiotics is commonplace in healthcare facilities. Even so, antibiotic-resistant infections remain a significant threat.

Researchers at the University of Michigan, however, suggest that fighting these so-called superbugs is being hindered by targeting individual multidrug-resistant organisms (MDROs) and neglecting the fact that there are multiple circulating MDRO species in healthcare institutions whose propagation is driven by competing risk factors.

In effect, the researchers suggest, using antibiotics to treat one particular MDRO may result in others. Rather than simply looking at one MDRO, healthcare practitioners need to consider such bacteria as part of an antibiotic-resistant ecosystem to see how MDROs interact with one other and with antibiotics.

“This single-species view of MDRO epidemiology does not reflect the complex reality; most healthcare facilities have multiple circulating MDRO species and individuals are often colonized by more than one MDRO,” they say. “Thus, interventions based on a single-species perspective can result in unintended consequences.”

That conclusion is based on a study of 234 nursing home patients in the Ann Arbor and Detroit areas. Forty percent of the frail elderly patients in the study had more than one MDRO living on their bodies. Patients who had specific pairs of MDROs were more likely to develop a urinary tract infection involving an MDRO.

The study, Network of Microbial and Antibiotic Interactions Drive Colonization and Infection with Multidrug-resistant Organisms, was published in the Proceedings of the National Academy of Sciences. Included in the study was a map of interactions among bacteria and classes of antibiotics.

Such mapping could eventually help healthcare providers. For instance, they could treat a patient with a specific antibiotic not only because of its ability to kill one MDRO, but also for its potential downstream impact on other MDROs on the patient or lurking nearby.

The study marked the first time this type of approach has been taken to understand the network of interactions that underlie antibiotic use and drive colonization with MDROs, the researchers say.

“Our analysis revealed a complex network of interactions: antibiotic use was a risk factor for primary MDRO colonization, which in turn increased the likelihood of colonization and infection by other MDROs,” wrote authors Joyce Wang, Betsy Foxman, Lona Mody and Evan S. Snitkin. “Our work demonstrates the existence of an underappreciated healthcare-associated ecosystem and strongly suggests that effective control of overall MDRO burden will require stewardship interventions that take into account both primary and secondary impacts of antibiotic treatments.”

Snitkin, a systems biologist in the Department of Microbiology and Immunology at the University of Michigan Medical School, explained in an interview that treating a patient with an antibiotic for one particular organism could cause other organisms to form.

“While you may be controlling one problem, you‘re potentially propagating other problems,” he says. “Unless you consider these secondary and tertiary effects, you might not be making a dent in the overall problem of reducing the prevalence of antibiotic resistance in these facilities in general.”

To put it into the simplest terms, consider the arcade game Whac-a-Mole, where players wielding a mallet try to hit moles which pop up at random from various holes in the playfield.

“It’s kind of like a Whac-a-Mole situation,” Snitkin agrees. “You try to knock down one problem organism and another one pops up.

“A more effective strategy might be taking a more global perspective and consider these secondary and tertiary impacts when making decisions and designing optimal ways to guide antibiotic treatment in these facilities,” he suggests. “Reducing the overall burden of antibiotic-resistant organisms in healthcare facilities will require strategies that consider both the intended and unintended consequences of antibiotic treatment decisions.”

Snitkin says research into this area is still in the early stages. The initial study involved the most functionally impaired nursing home residents who had implanted medical devices and were at the greatest risk for undergoing antibiotic treatment and also being colonized with MDROs.

Nearly two-thirds of the patients studied were treated with one or more of 50 different antibiotics during the study period. All the patients used a urinary catheter to empty their bladders for at least three days during the study period. This allowed the researchers to look at patterns of urinary tract infections, which among nursing home and hospital patients often arise from bacteria entering the bladder along a catheter.

The findings showed that colonization of such patients’ skin, noses and throats with common MDROs was not random.

“We observed a complex network of interactions, with acquisition of each of six different MDRO species being influenced by different sets of antibiotics, and primary MDRO colonization in turn increasing the risk of acquisition and infection by other MDROs,” says Wang, the lead author on the study and a postdoctoral fellow in Snitkin’s lab.

The study focused on two of the most dangerous MDROs — vancomycin- resistant Enterococcus (VRE) and methicillin-resistant Staphylococcus aureus (MRSA) — as well as four Gram-negative bacteria that have evolved resistance to two powerful antibiotics and are known to cause numerous infections in hospitals. They were Proteus mirabilis, Acinetobacter baumannii, Escherichia coli and Pseudomonas aeruginosa.

“Of the organisms we studied, each organism was influenced by at least one antibiotic and one other organism,” Snitkin says. “I think what really surprised us was that the organisms themselves influenced one another in ways we didn’t appreciate. It’s unclear right now what the basis is for that, what are the interactions happening between these organisms that are potentially facilitating one another’s propagation. We have additional work to do to learn how they might interact with one another with hopes we might be able to interrupt those interactions to control their spread.”

Additional studies are planned in other nursing homes and healthcare facilities to try to reproduce the results. Eventually the results could be included in antibiotic stewardship rules which Snitkin says could then be passed down to practicing physicians making decisions on what antibiotics to use.

Mody, a leader in studying infection transmission and prevention in nursing homes, is also involved in the follow-up study. It will take place in a different nursing home with residents who are not as ill as those in the initial study.

“Antibiotic use is highly prevalent and colonization of MDROs is common,” Snitkin says of people in the new study. “We want to know in this different population do these same sorts of rules apply. Or are there different rules dictated by the characteristics of individual patients and their medical history.”

While the focus on antibiotic usage has typically been on academic and acute-care hospitals, Snitkin says nursing homes have generally been an understudied part of the healthcare system.

“They (nursing homes) are increasingly appreciated to be critically important because there is a tremendous amount of antibiotic use,” he notes. “Just focusing on acute-care hospitals likely will not afford a solution to antibiotic resistance because our healthcare system is highly interconnected [with patients frequently moving back and forth between facilities]. If you don’t control the problem at a network level, at a healthcare network level, you‘re going to have a problem.”

In addition to Wang, Mody and Snitkin, the research team included Betsy Foxman, a longtime researcher in the epidemiology of antibiotic resistance and urinary tract infections at the University of Michigan School of Public Health.

Funding for the research study came from the Centers for Disease Control and Prevention and by a pilot grant from the U-M Claude D. Pepper Older Americans Independence Center, a research division of the University of Michigan Geriatrics Center funded by the National Institute on Aging of the National Institutes of Health.

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