Core Research Questions
At the MRSA Research Center, we are investigating the following research questions:
- How does MRSA spread? By touching another person? By sharing personal items? How easily does MRSA spread?
- Can you get infected from MRSA by touching a surface or object? If so, how long can MRSA last on a surface or object?
- How do you best treat a MRSA infection?
- Why do some people get really sick from MRSA and others don’t?
- Why is MRSA so resistant to antibiotics?
- Can we prevent MRSA infection with a vaccine?
- Why is community-associated MRSA spreading so quickly?
- What can we learn from whole genome sequencing about the transmission dynamics of MRSA among people in close contact?
- How does S. aureus evolve on the body of a human host? Does it change when it causes an infection?
Studies & Research Projects
The MRSA Research Center Lab collaborates with the University of Chicago Medical Center Clinical Microbiology Lab to obtain all MRSA strains isolated from patients on a daily basis. Upon receipt, the MRSA Research Center Lab subcultures the isolates, stores them in a freezer, and warehouses molecular and clinical information from these isolates in a database. The MRSA Research Center Lab analyzes the clinical and demographic characteristics of patients from whom the isolates were recovered, as well as the isolates' genetic characteristics and antimicrobial resistance profiles.
Do some strains of Staphylococcus aureus colonize people more commonly on one part of their bodies? We are examining the likelihood that S. aureus isolates having differed genotype backgrounds are more likely to be found at different places on the body. We are using data from testing of more than 1100 people in their household in the nose, the throat, and in the groin region for asymptomatic carriage of S. aureus. We have performed genotyping of all S. aureus obtained from these 1100 people, including assignment of each isolate to a multilocus sequence type (MLST), testing each isolate for carriage of the PVL toxin genes, and (for MRSA isolates only) assigning each isolates to a type of SCCmec element. The tested isolates include MRSA and methicillin-susceptible S. aureus. Some studies have shown that CA-MRSA isolates, including USA300, the genetic type that is the leading cause of CA-MRSA infections in the U.S., is often carried by individuals but is not found in their noses. If this is true, then screening of people for asymptomatic carriage—especially people at high risk for carriage of CA-MRSA isolates—may be best performed at a body site other than the nose.
CA-MRSA isolates are typically susceptible (can be killed by) a number of different classes of antibiotics. This includes a number of antibiotics that come in oral form, allowing for the treatment of uncomplicated CA-MRSA infections using pills, rather than more expensive intravenous antibiotics. There is a concern that if CA-MRSA strains develop resistance to commonly used oral antibiotics, such as clindamycin, doxycycline, or trimethoprim-sulfamethoxazole, as well as the newer and more costly antibiotic linezolid, we will have to change the recommendations for treating skin infections generally in the U.S. because in many settings, including urban U.S. emergency departments, MRSA is the leading cause of cultured skin infections. When skin infections are treated initially, the bacterium causing them is not yet known. Therefore, doctors have to choose a therapy (called an empiric therapy) that is likely to kill the most common causes of these infections. If MRSA is less likely to be killed by certain oral antibiotics over time, then practices have to change. We are performing a study to assess whether the antibiotic susceptibility profiles of genotypically and clinically defined CA-MRSA isolates obtained from patients at the University of Chicago are changing over time.
The goal of this project is to create a new agent-based model of MRSA that includes theoretically based and empirically derived variables representing behavioral features of the population (e.g., social networks) and the healthcare system. We are developing a flexible agent-based model scaling up in stages to the population of the Chicago metropolitan area, the first of which will include a corridor across the south side of Chicago and adjoining suburbs. We will use high-performance computing capabilities at the University of Chicago and Argonne National Laboratory to run individual model configurations thousands of times. A paper has been published from this study:
Macal CM, North MJ, Collier N, Dukic VM, Wegener DT, David MZ, Daum RS, Schumm P, Evans JA, Wilder JR, Miller LG, Eells SJ, Lauderdale DS. Modeling the transmission of community-associated methicillin-resistant Staphylococcus aureus: a dynamic agent-based simulation. J Transl Med. 2014 May 12;12:124.
This project is supported by the National Institute of General Medical Sciences, National Institutes of Health.
For more information on Models of Infectious Disease Agent Study (MIDAS), visit:
Map of Data Used in MRSA Modeling
|MRSA Modeling – Wide View||MRSA Modeling– Narrow View|
Despite the increasing incidence of CA-MRSA infections, the critical dynamic interaction of asymptomatic colonization and infection caused by this emerging pathogen and by other S. aureus genetic backgrounds has not been well studied. This interaction is important because patients frequently suffer from recurrent MRSA infections, and asymptomatic carriage of MRSA is a risk factor for subsequent MRSA infection. Recurrent MRSA infections in the skin or other tissues among SSTI patients with co-morbid conditions may in part therefore arise from persistent asymptomatic colonization with MRSA after drainage and antimicrobial therapy. However, little is known about the likelihood of persistent carriage of MRSA or methicillin-susceptible S. aureus (MSSA) after antimicrobial therapy for an ABSSSI or a minor cutaneous abscess. This study hypothesizes that persistent MRSA carriage in a population with a serious co-morbid condition (diabetes, coronary artery disease, obesity, peripheral vascular disease, and/or chronic kidney disease) will be less common after therapy with po linezolid for ABSSSIs and minor cutaneous abscesses than it is with po clindamycin. The objectives of this study are to: 1) determine the prevalence of asymptomatic carriage of S. aureus in patients with ABSSSIs and minor cutaneous abscesses after therapy with either linezolid or clindamycin at 40 days after the completion of therapy; and 2) determine the efficacy of linezolid vs. clindamycin in the empiric therapy of ABSSSIs and minor cutaneous abscesses, as well as the genotypic spectrum of S. aureus isolates causing these SSTIs and colonization in the target patient population before and after therapy.
This project is supported by Pfizer.
For more information on this linezolid or clindamycin study, visit: http://clinicaltrials.gov/
New Antibiotics to Treat MRSA Infection by Targeting VraSR, a conserved two-component signal transduction system in Staphylococcus aureus
An exciting project is underway at the MRSA Research Center Laboratory to identify new antibiotics that can be combined with methicillin (and modern day replacement- oxacillin) to make oxacillin stronger in the therapy against MRSA. Such drugs are used in combination with oxacillin and are referred to as potentiators. The discovery that a conserved signal transduction system in S. aureus, called vraSR, is necessary for MRSA isolates to be resistant to methicillin inspired this project. Our idea is to inhibit VraSR in MRSA isolates so that the MRSA isolates are more susceptible to methicillin and oxacillin antibiotics. We have already shown that mice infected with an MRSA mutant strain lacking vraSR genes can be treated with oxacillin successfully because the mutants are more susceptible to oxacillin. To identify oxacillin potentiators, we have screened a library of 25,000 small molecules that have drug like properties for their ability to inhibit vraSR operon expression and inhibit growth in the presence of small subinhibitory amounts of oxacillin. Our hope is that the inhibitor of VraSR together with oxacillin will provide a combination that will prove deadly to the previous MRSA strain and restore the use of oxacillin against MRSA. We have had exciting success in this project. We have identified a scaffold that inhibits the vraSR operon expression, potentates oxacillin and binds to the purified VraS kinase. We have received federal funding from the National Institutes of Health to test the lead candidates against multiple strains of MRSA. Advanced testing will include pharmacokinetic and pharmacodynamic testing followed by efficacy testing in experimental lung and skin infection in mice.
This project is supported by the National Institute of Health and is being done in collaboration with investigators at the University of Illinois in Chicago and at St. Jude’s Hospital in Memphis, TX.
MRSA infections often recur in patients, but it is not known which patients are at highest risk for recurrence nor whether CA- or HA-strains are more likely to cause recurrence. In the era of CA-MRSA, it is not known if patients with persistent carriage of MRSA are at elevated risk of recurrent MRSA infections. There are interventions that may decrease the likelihood of recurrent MRSA infections in an individual: decolonization protocols, cleaning of fomites, antibiotic therapies, and vaccines are all potentially relevant avenues for the future control of MRSA in the community. Each of these modalities will require further study to assess its efficacy and safety. Patients with recurrent MRSA disease are likely to benefit from such interventions, and the control of MRSA infections in this population may be critical to stemming the dissemination of CA-MRSA in the U.S. In this a two-part study, using a collection of >13,800 stored clinical S. aureus strains, obtained through surveillance at the University of Chicago Medical Center (UCMC), the MRSA Research Center will attempt to define risk factors for recurrent MRSA infections. First, using existing surveillance data from UCMC in 2003-2009, in a case-control study treating those with multiple infections as the cases and those with a single infection as controls, the MRSA Research Center will examine the following as risk factors for re-infection: anatomic site of first infection, genotype of first and subsequent infecting MRSA strains including CA- and HA-MRSA strain characteristics, patient demographic characteristics, previous exposures to the healthcare system, and patient comorbidities. Second, nesting a prospective cohort study of recurrent MRSA infections in surveillance at UCMC, the MRSA Research Center will enroll 400 patients with incident MRSA infections and monitor them for two years. The MRSA Research Center will determine how frequently these patients have recurrent MRSA infections, how commonly they seek medical attention for the infections, the presence of the risk factors for re-infection listed above, and the genotypes of MRSA strains associated with infections and any identified asymptomatic colonization to assess the role of chronic colonization in the recurrence of MRSA infections.
This project is supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health.
We assessed the colonization rate among Emergency Department attendees by using a novel approach. The principal innovations were culturing several body sites, the nose, the throat and the perianal skin and the use of an enrichment step. As for the household contact study, this involved incubation of the swab obtained from the enrollees in broth overnight and culturing an aliquot of the broth on selective S aureus agar the next day.
Our findings reported in the J Clin Micro were that S aureus colonization rates were extraordinarily high in both patients and controls. The controls, Emergency Department attendees whose reason for seeking care did not seem related to any infectious disease, were also colonized at an extraordinarily high rate, a rate that did not differ statistically from that found in the patients. However, molecular typing of the isolates revealed that important differences existed between colonizing strains in the two groups.
Controls were colonized by S aureus strains that more likely were not found as the cause of an infection in any patient of which we were aware. These studies indicated that 1) asymptomatic S aureus colonization was nearly universal and much more common than believed, 2) Colonizing strains were often different in terms of genetic background) than those responsible for infection. S aureus is therefore often a commensal and not a pathogen, at least among these strains. 3) polyclonal S aureus colonization was common.
Kumar N, David MZ, Boyle-Vavra S, Sieth J, Daum RS. High Staphylococcus aureus colonization prevalence among patients with skin and soft tissue infections and controls in an urban emergency department. J Clin Microbiol. 2015 Mar;53(3):810-5.
To study index patients and their household contacts with a longitudinal profile, we enrolled patients seeking care at the emergency department, both adults and children, with skin infections at the University of Chicago Medical Center and at the Emergency Department of the Harbor Campus of the University of California at Los Angeles. With RO1 support from the National Institute of Allergy and Infectious Diseases (NIH), we conducted a study that solicited information about the index patients, the household contacts and behaviors that increased their risk for infection. All household members and selected fomites were cultured repeatedly and at multiple sites. Swab culture enrichment was performed by incubating swabs from patients in broth overnight and plating an aliquot of broth on selective agar (Chrome Agar Staph aureus) the next day. Fomites were cultured with a Spongesicle, agitated in a Stomacher, incubated overnight and similarly plated the next day. 354 households in Chicago and Los Angeles were enrolled. In-person visits were performed at baseline and three and six months later.
Many lessons have been learned (1-3) and more data are forthcoming. Individuals were colonized with S. aureus at high rates. Polyclonal colonization was common. USA300 colonization was frequent as was colonization with other S. aureus genetic backgrounds. Fomites were frequently contaminated.
A second household contact study is planned, in 2017, pending funding.
- Miller LG, Eells SJ, David MZ, Ortiz N, Taylor AR, Kumar N, Cruz D, Boyle-Vavra S, Daum RS. Staphylococcus aureus skin infection recurrences among household members: an examination of host, behavioral, and pathogen-level predictors. Clin Infect Dis. 2015 Mar 1;60(5):753-63.
- Eells SJ, David MZ, Taylor A, Ortiz N, Kumar N, Sieth J, Boyle-Vavra S, Daum RS, Miller LG. Persistent environmental contamination with USA300 methicillin-resistant Staphylococcus aureus and other pathogenic strain types in households with S. aureus skin infections. Infect Control Hosp Epidemiol. 2014 Nov;35(11):1373-82.
- Miller LG, Eells SJ, Taylor AR, David MZ, Ortiz N, Zychowski D, Kumar N, Cruz D, Boyle-Vavra S, Daum RS. Staphylococcus aureus colonization among household contacts of patients with skin infections: risk factors, strain discordance, and complex ecology. Clin Infect Dis. 2012 Jun;54(11):1523-35
- Alam MT, Read TD, Petit RA 3rd, Boyle-Vavra S, Miller LG, Eells SJ, Daum RS, David MZ. Transmission and microevolution of USA300 MRSA in U.S. households: evidence from whole-genome sequencing. MBio. 2015 Mar 10;6(2):e00054.
|Households may be contaminated with MRSA.|
Treatment Study: Randomized, Double Blind Trial of Clindamycin, Trimethoprim-Sulfamethoxazole, or Placebo for Uncomplicated Skin and Soft Tissue Infections Caused by Community-Associated Methicillin-Resistant Staphylococcus aureus
The University Of Chicago MRSA Research Team has been evaluating the best way to treat patients with skin infections who seek care at our institution. Enrollment has been in the Emergency Department – both adult and pediatric, and started in 2009. The trial has been funded by the National Institute of Allergy and Infectious Disease. The Principal Investigator on the NIAID grant has been Henry ‘Chip’ Chambers MD of the University of California at San Francisco.
Two trials have been conducted. The first trial has been completed. It offered enrollment to adults and children older than six months of age and younger than 85 years of age. Enrollment was offered to individuals with an abscess > 5 cm in diameter (> 3.0 cm in patients 6 - 11 months of age and > 4.0 cm in patients 1 - 8 years of age). Enrollment was also offered to patients attending the Emergency Room with purulent and non-purulent cellulitis and individuals with multiple skin infections. All patients with an abscess received incision and drainage following which enrollees were randomized to receive a 10-day course of clindamycin or trimethoprim/sulfamethoxazole. Enrollment is complete and the study has been reported (1). The second study also has completed enrollment. Enrollees had smaller abscesses, had no cellulitis, and did not have multiple lesions. Patients in this second study were randomized to receive clindamycin, trimethoprim/sulfamethoxazole, or placebo. Data analysis for this second trial is in progress.
- Miller LG, Daum RS, Creech CB, Young D, Downing MD, Eells SJ, Pettibone S, Hoagland RJ, Chambers HF. Clindamycin versus trimethoprim-sulfamethoxazole for uncomplicated skin infections. N Engl J Med. 2015 Mar 19;372(12):1093-103.
For more information on this clinical trial visit:
Coordinating with the Treatment Study, the MRSA Research Center is identifying human genetic markers predisposing to S. aureus infection.
This project is supported by the National Human Genome Research Institute.
This study is aimed at discovering (a) what it is about USA300 that has made it so kinetically and biologically fit and (b) why USA300 has become the most prominent MRSA background in most areas in the United States. The reasons why this strain has become so dominant are not clear. We have hypothesized that (a) USA300 is a strain that has benefited from a disorder of virulence gene regulation and (b) virulence genes are up-regulated in this gene. We have already published a paper that has shown that USA300 strains are more virulent than other strains. We have also shown in the same paper, published in the Journal of Infectious Diseases, that key virulence genes and P-global regulators such as AGR and SAE are up-regulated in these strains. Investigations are in progress to examine microarray expression techniques and expression of all genes in the USA300 genome to compare with a now extinct USA400 background to see if the USA300 virulence genes are up-regulated in comparison. This study is ongoing.
|The appearance and dominance of the USA300 MRSA strain.|
The Epidemiology of Staphylococcus aureus at the University of Chicago, 2006-2014: A Data Warehouse Study
Using administrative data from the newly available Data Warehouse at the University of Chicago Medicine, in this project we are examining trends in the incidence of MRSA and methicillin-susceptible Staphylococcus aureus infections during the past decade. We will stratify our analyses by community-associated and health care-associated infections, infections in different age groups and infections at different sites of care at the medical center. This longitudinal study will use laboratory, billing and other administrative data to examine the most recent trends over time in the epidemiology of S. aureus, including changes in demographics and antimicrobial susceptibility. This project has resulted a manuscript is in preparation on S. aureus infections in children and adults, 2006-14. Another manuscript has been published using this dataset:
Morgan E, Daum RS, David MZ. Decreasing incidence of skin and soft tissue infections with a seasonal pattern at an academic medical center, 2006–2014. Open Forum Infectious Diseases 2016;3(4):doi:10.1093/ofid/ofw179.
We will study the trends in skin and soft tissue infections (SSTIs) in various demographic strata among emergency department patients using administrative data from Vidant. This will update studies that demonstrated a rapid increase in the incidence of SSTIs in 2000-2010.
In a systematic review of the international biomedical literature, in a project led by Michael David, we are abstracting genotyping data from all published studies of MRSA, regardless of language, in which a reproducible and standardized genotyping system is used to classify MRSA isolates. This project has resulted in a growing database (the MRSA TypeCat) that provides the following data for each reported MRSA isolate, when it is included in the published source:
- Year of acquisition (a range is sometimes given in the publication, and this is recorded if a single year is not)
- Geographic location of isolation (country / region, province or state / city, county or town)
- Source of culture (human body, specific species of animal or fomite)
- In cases of animal or human source, whether it was from a colonization or an infection culture
- For an infection culture, some specific types of infection (bacteremia, skin or soft tissue infection, pneumonia)
- Specific isolate identifier
- Genotyping information (MLST, spa typing, PFGE type, MLVA type, SCCmec type, dru type)
- Presence or absence of the PVL genes and ACME elements
- Publication information (first and last author, journal name, publication year, volume, & pages)
- Notes on the study from which the isolate was obtained, including GenBank Accession numbers for any isolates that have undergone whole genome sequencing
As of March 1, 2017, the MRSA TypeCat included 181,000 isolates collected in 110 countries abstracted from 1,835 articles published between 2000 and 2015. We anticipate that the MRSA TypeCat will be complete include all relevant articles indexed by PubMed through December 31, 2015 by May 2017. The TypeCat will be a resource that will enable us to track the emergence of new strain types and their spread around the globe over time. Also, it will serve as an index of unusual strain types that may enhance the ability of researchers to collaborate with one another. An initial study using the MRSA TypeCat, on the emergence of USA300 MRSA in the U.S., was published in Emerging Infectious Diseases:
Carrel M, Perencevich EN, David MZ. USA300 Methicillin-Resistant Staphylococcus aureus, United States, 2000-2013. Emerg Infect Dis. 2015 Nov;21(11):1973-80.
Dr. Phoebe A. Rice, affiliated faculty, is examining, at a molecular level, the mobility of the SCCmec element. Insertion of this DNA element into host chromosome turns garden-variety S. aureus into MRSA. The initial phase of this project will develop: 1) an in vitro system for studying the relevant SCCmec-encoded DNA recombinases with purified components, and 2) in vivo systems for studying these proteins in S. aureus and E. coli strains. The long-term goals are to understand the mechanism and regulation of these recombinases at the atomic level, leverage this knowledge to understand the horizontal transmission of SCCmec, and devise ways to stop its spread into new strains and/or trigger its excision and loss from the MRSA genome.
This project is supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health.