MRSA over 3 decades: A pathogen with ‘devastating complications’

Issue: September 2017

To mark our 30th anniversary, Infectious Diseases in Children will be examining some of the infectious diseases that have defined and changed the field over the past 3 decades.

MRSA isolates were once primarily found only in hospitals and other health care settings in the United States. However, over the course of 20 years, there had been a significant increase in the number of MRSA infections reported in the community setting among people who had little or no exposure to the health care system.

The percentage of nosocomial Staphylococcus aureus isolates that were identified as methicillin-resistant continued to rise during the 20-year span — from 2% in 1974 to approximately 50% in 1997, according to a review article published in The New England Journal of Medicine in 1998.

But as the number of overall MRSA cases increased during those 2 decades, so did the prevalence of community-acquired cases without an identifiable risk. According to a study published in JAMA that same year, the number of community-acquired MRSA cases increased from 10 per 100,000 admissions in 1988-1990 to 259 per 100,000 admissions in 1993-1995.

“Subsequent outbreaks of MRSA were reported across the U.S. among individuals in the community who did not have prior health care exposures and were otherwise healthy,” Kyle J. Popovich, MD, MS, an infectious disease physician at Rush University Medical Center, told Infectious Diseases in Children. “By 2006, Moran and colleagues published a study in The New England Journal of Medicine demonstrating that MRSA was the most common cause of skin infections being seen in emergency rooms across the nation, and USA300 was often the causative strain.”

During the mid-1990s and up to the early 2000s, the epidemiology of MRSA was punctuated by an explosion of mostly soft tissue infections among community-dwelling healthy individuals with no prior health care contact, according to Vance Garrison Fowler, MD, a professor of medicine at Duke University School of Medicine and a member of Duke Clinical Research Institute.

Not only was the epidemic unique in the epidemiology of community-acquired infection, Fowler said, but it was also distinct in the microbiology of the organism.

“It really came from nowhere. It was a bit more genetically distinct than other clones, and it led to a virtual explosion of MRSA soft tissue infections,” Fowler said.

Fowler noted that rates of infections with USA300 clones have gradually declined both inside and outside the hospital setting beginning in the mid-2000s.

“It’s a mystery in that we really don’t know where the clone came from and we really don’t know where the clone went,” he said.

Although MRSA is a global pathogen, its incidence varies worldwide, according to C. Buddy Creech, MD, MPH, an associate professor of pediatric infectious diseases and director of the Vaccine Research Program at Vanderbilt University School of Medicine.

“For instance, in Europe, there have been major issues with health care-associated MRSA, leading some countries to adopt very sophisticated screening protocols for patients admitted to the hospital.”

A positive trend

There were an estimated 30,800 fewer invasive MRSA infections reported in the U.S. in 2011 compared with 2005, according to a study published in JAMA Internal Medicine, and findings from the AWARE surveillance program indicated that the MRSA rate decreased from 47.2% in 2009 to 43.6% in 2015. Additional data showed that the MRSA rate decreased further to 42.2% in 2016.

“We have learned a lot over the last several years about the importance of horizontal infection control strategies,” Popovich said. “These are prevention strategies that are not pathogen-specific but rather target multiple pathogens. Examples include hand hygiene, environmental cleaning, contact precautions and chlorhexidine gluconate bathing. Bundles of interventions have led to reductions in acquisition and infections due to multidrug-resistant organisms. Vertical infection control strategies — those that are pathogen- or MRSA-specific — have also been utilized by some health care facilities to try to reduce infection and spread of MRSA.”

However, Popovich noted that studies have also shown that the decrease in MRSA is less significant in the community setting, further highlighting an important area of research.

Vancomycin resistance

“There’s a lot of controversy around vancomycin,” Fowler said. “Generally, vancomycin has been a mainstay antibiotic for 3 or 4 decades, and the fact is that it remains an excellent antibiotic even today. We use it because we traditionally have had to — not because we necessarily want to — because it has some properties that are suboptimal, but it is a reliable drug.”

Although vancomycin-resistant MRSA is relatively rare, according to Popovich, there are reports of vancomycin-intermediate S. aureus, as well as strains that “creep” toward the upper limit of susceptibility.

“Some studies have suggested an increased chance of failure with vancomycin in these cases, while other studies have suggested that failure isn’t due to antibiotic selection but rather due to more difficult-to-treat strains,” Popovich said. “While this remains an unresolved issue, the major principal of therapy for MRSA infections is ensuring adequate source control in conjunction with antibiotic therapy.”

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Although vancomycin is active against nearly every strain of S. aureus, it is sometimes not the most effective antibiotic because of side effects and because it kills bacteria more slowly than other antibiotics, according to Creech.

“What I’ll often tell trainees is that, ‘vancomycin is really not that amazing of a drug. It’s nephrotoxic, it often takes days to reach therapeutic levels in the bloodstream, and it doesn’t reach certain tissues — such as bone or the lungs — as effectively as other drugs. As a result, when you put it all together, you wonder, why do we even use it? It’s mainly because every strain of S. aureus, within reason, is going to be killed by it eventually. But we can do better.’”

‘A uniquely problematic pathogen’

Although there are concerns of MRSA becoming fully resistant to antibiotics, Fowler said his first concern with the disease moving forward is that it is so common that clinicians tend to accept the damage that it inflicts in patients.

“We as a subspecialty need a healthy dose of concern with every case of S. aureus infection that we see,” he said. “Where I grew up, the saying was that ‘It’s the snake you don’t see that you have to worry about.’ The same is true for S. aureus in general, and MRSA in particular. As consultants, our role is to consider and identify the devastating complications that might be clinically occult early on. If we look at a typical ID consultant’s rounds in the U.S., most of their work-related responsibilities are going to involve this pathogen in some form. In some practices, 40% to 60% of patients that physicians see are going to have some variation of this pathogen in a whole host of different and devastating presentations.

“When you contrast that with Zika or Ebola, you may see a handful of those in a career,” he added.

What sets MRSA apart from other diseases is the heterogeneity of diseases that it can cause, Fowler said. MRSA can cause pneumonia, bone and joint infections, heart valve infections and is one of the leading causes of prosthetic device infections.

“It’s the breadth of devastation that really makes MRSA such a uniquely problematic pathogen,” he said. “Many bugs are resistant; few bugs are as broadly devastating as MRSA.”

Vaccine development

Over the last 30 years, Creech said, there has been significant interest in the development of an S. aureus vaccine.

“People have strong opinions,” he said. “Some say that because S. aureus is the most common bacterial infection in the U.S., we should vaccinate everybody. But others say it is a part of our microbiome and it’s supposed to be there, and instead of trying to build a vaccine that would be for everyone, let’s have a vaccine that could be given for those who are at highest risk. These patients might include those who are immunocompromised or those who are undergoing surgical procedures — particularly those who are receiving device implants or hip replacements.”

Creech said he envisions the prevention of infection after surgery to be the first area of development for a vaccine.

“What we really need are better therapeutic options that are aimed specifically at disrupting the virulence of the organism, not simply to kill it like an antimicrobial, but to blunt some of the physiologic effects that we see in S. aureus,” he said. “Many of us are working to take what the human host does after infection, pull out those antibodies and figure out ways that we can deliver some of those antibodies to those who are at risk for, or infected with, S. aureus.” – by Ryan McDonald

References:
Adcock PM, et al. J Infect Dis. 1998;doi:10.1086/517478.
Dantes R. JAMA Intern Med. 2013;doi:jamainternmed.2013.10423.
EDMA. Screening programmes for Hospital Acquired Infections. Available at:
https://www.vdgh.de/media/file/199.4_anlage-1e-fact-sheet-nosocomial-jun07.pdf. Accessed June 20, 2017.
Herold BC, et al. JAMA. 1998;doi:10.1001/jama.279.8.593.
Moran GJ, et al. N Engl J Med. 2006;doi:10.1056/NEJMoa055356.
Sader H, et al. Antimicrobial susceptibility trends among Staphylococcus aureus from US hospitals: Results from 7 years of the Ceftaroline (AWARE) Surveillance Program (2009-2015). Presented at: ASM Microbe; June 1-5, 2017; New Orleans.
Suaya JA, et al. BMC Infect Dis. 2014;doi:10.1186/1471-2334-14-296.
Suntharam N, et al. J Clin Microbiol. 2001;doi:10.1128/JCM.39.4.1669-1671.2001.

Disclosures: Creech reports receiving grant funding from GlaxoSmithKline and Pfizer, as well as serving as a consultant for Theravance Biopharma. Fowler reports ties with several pharmaceutical companies. Popovich reports no relevant financial disclosures.