Pathogen and Treatment Paradigms for Multidrug-Resistant Infections

The increased prevalence of multidrug-resistant (MDR) infections over the past several years has become a major burden for patients, hospitals, and long-term care facilities. Optimizing antibiotic stewardship programs and improving the transition of care between hospitals and long-term care facilities will be important for improving management of MDR infections, according to panelists who participated in a Contagion^® Peer Exchange panel.

“We’re facing a real crisis here,” said moderator Peter L. Salgo, MD. “Our antibiotics are becoming less effective, and we’ve got diseases that we’re having a lot of trouble treating.”

OVERVIEW OF MULTIDRUG-RESISTANT INFECTIONS

The Centers for Disease Control and Prevention (CDC) estimates that MDR pathogens infect 2 million patients per year and are the cause of 23,000 mortalities,¹ and the panelists noted that the number has increased over the past several years. “Pick your favorite organism,” said Jason Pogue, PharmD. “If you look at resistant versions of that bug, the numbers are going up over time, and that’s why it’s an urgent threat to us,” he said.

Additionally, infections that require multiple treatment attempts are burdensome to patients and hospitals, according to Sandy J. Estrada Lopez, PharmD. “Perhaps we had to try 2 things, 3 things, 4 things, and then they did eventually work,” she said. “But the cases where there’s extended length of stay, extended cost, or need to stay in the hospital, or that have repeat visits are becoming more common.”

Andrew Shorr, MD, noted that crude mortality rates for infections with highly resistant gram-negative organisms are approaching rates seen in the preantibiotic era, and the prevalence of MDR infections will continue to increase with the aging population, changes in the epidemiology of pathogens, and increasingly aggressive use of immunosuppression for nearly every disease state.

“People are living longer, and they’re not dying of their heart failure [or] renal disease,” he said. “This is not going away, and I think we’ve all lamented it. I think the problem now is we’ve got to figure out how to solve it.”

THE CAUSES AND IMPACT OF MULTIDRUG-RESISTANT INFECTIONS

Causes

Most experts agree that frequent use of antibiotics is a key contributor to the increase in MDR infections, but they disagree about whether antibiotics are overused. While Drs. Shorr and Salgo agreed that the increased prevalence of resistant infections is due in large part to overuse, Dr. Pogue stated that appropriate use of antibiotics would still lead to the development of resistance.

“Sure, we could mitigate it a little bit by more appropriate use [and] limiting unnecessary antibiotic use,” he said. “But it’s natural selection…we would expect this to occur.”

Dr. Shorr argued that clinicians are the primary contributors to the problem and should be responsible for finding solutions moving forward. “This has been like watching a slow-motion car crash for a generation, and we’re still playing catch-up. We’ve created the problem; we have to fix the problem,” he stated.

Debra Goff, PharmD, added that antibiotic use in animals accounts for about 70% of antibiotic prescriptions in the United States and may contribute to the resistance seen in humans. “When you look at the animal-to-human transmission of resistance, there’s a big component right now of who’s to blame,” she said. “Health care providers are part of it, but responsible use in the animal sector is another part.”

Clinical and Community Impact

According to Dr. Pogue, the clinical impact is best illustrated by comparing patient outcomes between infections with MDR organisms and the drug-susceptible form. “What you’re going to find…[is that] mortality rate doubles, and if the patient survives, length of stay is double, as is the need for extra care afterward,” he said. “And from the hospital standpoint, there’s a cost associated with every single one of those things.”

Drs. Pogue and Goff also pointed out that the spread of resistant infections into the community can have devastating effects on otherwise healthy individuals. “We’re seeing patients who have never had health care exposure acquire their first Escherichia coli [urinary tract infection that is] multidrug resistant,” said Dr. Goff.

MULTIDRUG-RESISTANT INFECTIONS: CURRENT PATHOGEN AND TREATMENT PARADIGM

With the increased burden of MDR infections, much research has focused on the development of new antibiotics over the past 10 years, including a few new agents developed over the past 2 to 3 years that target gram-negative bacteria, such as multidrug-resistant Pseudomonas and carbapenem-resistant Enterobacteriaceae (CRE).

Dr. Shorr cautioned that none of the novel agents are a “cure-all” and that the agents targeted toward gram-negative pathogens have unique strengths and weaknesses. He explained that clinicians need to consider the role of a given antibiotic at a particular hospital and whether it fits in with the concept of antibiotic/microbial stewardship.

“They all have different spectrums of activity, and not 1 of them is going to be the right answer for every hospital,” he said. “It’s one of these issues where you actually have to do a lot of thinking and cognition to decide how you’re going to utilize these on your formulary, if at all.”

However, Dr. Goff pointed out that the selection of antibiotics is often managed by a stewardship program rather than the physician’s belief of what will be most effective for treating the patient. “Most of the time, you’re prescribing in the moment. You’re not thinking about the impact on society.”

She and the other panelists agreed that reconciling the responsibilities of treating the patient and considering society will be the next challenge moving forward and that stewardship programs will need to have input from multiple disciplines.

“The different perspectives are a huge thing to appreciate,” said Dr. Pogue. “That’s why your stewardship program has to have all the key players on it. It can’t just be [infectious disease] and pharmacy that [are] making these decisions.”

GRAM-NEGATIVE NOSOCOMIAL INFECTIONS: SYSTEMIC RISK

Although multiple factors, such as a suppressed immune system and hospital interventions that allow for growth of biofilms (such as insertion of tubes and lines), increase the risk for gram-negative MDR infections, prior antibiotic exposure is the main factor that selects out resistant pathogens, according to Dr. Shorr.

He said that clinicians need to consider the epidemiology of their hospital because the risk factors are not specific for a particular pathogen. “If you don’t have CRE [at the hospital], the patient is not at risk for CRE. But it would also be helpful to know sometimes what the patient has been colonized or infected within the process,” he stated.

The panelists also discussed the high risk of resistant infections in nursing homes, long-term acute care hospitals (LTACHs), and skilled nursing facilities that are caused by the repeated transfers from the hospital to the long-term care facility. “Those places breed resistance because there’s no focus necessarily on good infection prevention and very little focus on antibiotic prescribing,” said Dr. Shorr.

Additionally, antibiotics are often continued in LTACHs even if an alternate diagnosis is found, said Dr. Shorr. “[In this situation], we stop these antibiotics in the hospital, but in those facilities, because you can’t get the monitoring as closely, you’re afraid that if you stop too soon, there might be a consequence.”

The panelists also noted that poor communication between the LTACH and the hospital may contribute to the continuation of antibiotics beyond the recommended time frame. “Patients going from the hospital to the LTACH [are] on antibiotics,” said Dr. Lopez. “Maybe they’ve already been on antibiotics for 12 days [and] they need 3 more days. For whatever reason, that stop date gets lost in translation when they leave the hospital.”

The panelists concluded that improving the transition of care between the hospital and long-term care facilities will be a key area of advancement to reduce the burden of antibiotic resistance on patients and the health care system. “At some point, we have to marry each other because we’re never going to solve the problem,” said Dr. Goff. “There’s a social responsibility to doing it right.”

Reference

1. Antibiotic/antimicrobial resistance. CDC website. cdc.gov/drugresistance/about.html. Updated September 15, 2017. Accessed March 8, 2018.