The Ongoing Threat of Methicillin-Resistant Staphylococcus aureus

(See the Major Article by Guthrie et al on pages 2071–81.)

Methicillin-resistant Staphylococcus aureus (MRSA) has a long and troublesome history of causing human disease, debility, and death. After the introduction of methicillin in 1960, methicillin-resistant strains were described soon thereafter in England in 1961 [1]. In 2009, Chambers and DeLeo described 4 historical waves of resistance in S. aureus [2].

The first wave of antibiotic resistance came with the introduction of penicillin in the 1940s [3]. Methicillin resistance marked the beginning of the second wave in the 1960s and, with it, the introduction of the staphylococcal chromosome cassette mec I (SCCmecI). In the 1960s and 1970s, these MRSA-I strains were a scourge primarily of hospitalized patients and were responsible for multiple health care-associated outbreaks in the United States and Europe [4, 5]. In the late 1970s, the third wave began with the appearance of strains carrying SCCmecII and SCCmecIII that continued to circulate in health care-associated settings worldwide [6]. Finally, in the mid-1990s, there was a dramatic shift from health care-associated infections to infections found in community settings, which represented the beginning of the fourth wave [7–9]. Suddenly, there was a dramatic increase in community-acquired cases in healthy individuals who lacked prior health care contact. These community-acquired strains harbored the SCCmecIV cassette, which moved more easily than its predecessors and bore little resemblance to the hospital-acquired strains that came before it [10].

Each of these waves was marked by clones that rose to prominence until novel clones took their place. Clonal complex 5 (CC5) and clonal complex 8 (CC8) came to represent the most common hospital-acquired and community-acquired MRSA strains in the United States, respectively. Other clonal complexes were common in Europe and elsewhere, but the CC8 clone USA300 became the primary cause of community-acquired MRSA after emerging between 1999 and 2001 [11]. USA300 S. aureus strains spread until they accounted for the majority of skin and soft tissue infections in patients presenting to emergency departments in the United States [12, 13]. At one point, MRSA infections caused more deaths annually than any other infectious disease, including HIV/AIDS, viral hepatitis, and influenza, combined in the United States [14, 15]. Multiple epidemic waves of MRSA have been fueled by the acquisition of mobile genetic elements via horizontal gene transfer. This adaptation, combined with the relatively high rate of asymptomatic carriage in the developed world, has made MRSA a particularly persistent adversary [16, 17].

The emergence and successful spread of the CC8 epidemic clone has highlighted the need for innovation in therapeutics and antibiotics. MRSA was declared a continued threat to public health by the Centers for Disease Control in 2013 and the President’s Council of Advisors on Science and Technology in 2014 [18, 19]. For many years, the outbreak of USA300 CA-MRSA was largely considered to be a problem contained within the United States, with rates of these particular strains remaining low in Europe and elsewhere.

In the past decade, there has been a gradual shift in focus from MRSA to multidrug-resistant (MDR) gram-negative infections. In some instances, MRSA was written off as less concerning and largely manageable with new antibiotics, while the growing threat of MDR gram-negatives provided a new subject area on which funding agencies and scientists could focus. Further, novel threats such as Candida auris and the now global pandemic of SARS-CoV-2 have justifiably captured our global attention. While attention may have shifted away from MRSA for a variety of reasons, its assault on human health has not relented. Though broadly listed as “one of many” serious threats in the most recent Center for Disease Control Antimicrobial Resistance Threats report in 2019, MRSA is associated with more deaths than many of the urgent threats in that report [20]. For those who continue to study this deadly pathogen, MRSA still represents a constantly evolving challenge—a pandemic no more contained now than it has ever been.

The work of Guthrie et al in this issue of The Journal of Infectious Diseases demonstrates that we still have much to learn about how MRSA spreads around the globe [21]. Through the use of whole-genome sequencing and bioinformatics, combined with traditional bench and clinical microbiology, researchers at multiple hospitals and public health agencies in Ontario successfully evaluated the changing population of MRSA isolates in their region. The authors demonstrate that, in Ontario, MRSA populations are shifting from HA-MRSA to CA-MRSA strains. This shift is a significant change from just over 23% CA-MRSA in 2010 to 43% CA-MRSA in 2016, and parallels the shift seen in the United States from the early 1990s to the early 2000s. The increase in CC8 strains is 1.5 times, with a corresponding decrease in CC5. Additional changes observed in CC30 and CC59 prevalence are worthy of continued investigation. The authors then tied the genomic and phylogenetic data back to the clinical antimicrobial resistance picture, showing significant increases in resistance to several antibiotics as a direct result of this shift in clonal complexes. Finally, they close the loop by showing the true power of whole-genome sequencing to identify both the overall genetic diversity of the MRSA population and the small related clusters in hospital settings. A diversity of clonal backgrounds in the Ontario strain population demonstrated a changing landscape between 2010 and 2016. The authors identified several small related clusters of strains, 3 of which were health care related. This study demonstrates the potential power of continual active surveillance of infections, using whole-genome sequencing to provide detailed analyses of strain relatedness.

MRSA presents unique challenges because there is a high level of asymptomatic colonization. Further, clonal pools of isolates may exist within a community, making infection control investigations difficult [22]. Understanding infections at the whole-genome level is truly the future of high-resolution infection control. As our current challenges are proving to us, there are distinct advantages to understanding the diversity of infections present in a clinical population, and in monitoring changes in those populations over time. We must be able to identify new outbreaks as they occur in order to deliver high-quality and effective health care. Moreover, as the work by Guthrie et al demonstrates [21], the power of multicenter collaborations to deliver comprehensive population-based datasets for studying infectious disease cannot be overstated. MRSA has been, and will continue to be, with us, and it will continue to adapt to every new tool in our armamentarium. We have no choice but to continue to study this deadly pathogen. We ignore it at our own peril.

Note

Potential conflicts of interest. S. W. L. reports personal fees from Biofire Diagnostics, LLC, outside the submitted work. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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