Publications by authors named "Robert S Daum"

104 Publications

Identification of Small Molecules Exhibiting Oxacillin Synergy through a Novel Assay for Inhibition of Expression in Methicillin-Resistant Staphylococcus aureus.

Antimicrob Agents Chemother 2019 09 23;63(9). Epub 2019 Aug 23.

Center for Biomolecular Sciences and Department of Medicinal Chemistry & Pharmacognosy, University of Illinois at Chicago, Chicago, Illinois, USA

Methicillin-resistant (MRSA) strains that are resistant to all forms of penicillin have become an increasingly common and urgent problem threatening human health. They are responsible for a wide variety of infectious diseases ranging from minor skin abscesses to life-threatening severe infections. The operon that is conserved among strains encodes a three-component signal transduction system () that is responsible for sensing and responding to cell wall stress. We developed a novel and multifaceted assay to identify compounds that potentiate the activity of oxacillin, essentially restoring efficacy of oxacillin against MRSA, and performed high-throughput screening (HTS) to identify oxacillin potentiators. HTS of 13,840 small-molecule compounds from an antimicrobial-focused Life Chemicals library, using the MRSA cell-based assay, identified three different inhibitor scaffolds. Checkerboard assays for synergy with oxacillin, reverse transcriptase PCR (RT-PCR) assays against expression, and direct confirmation of interaction with VraS by surface plasmon resonance (SPR) further verified them to be viable hit compounds. A subsequent structure-activity relationship (SAR) study of the best scaffold with diverse analogs was utilized to improve potency and provides a strong foundation for further development.
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http://dx.doi.org/10.1128/AAC.02593-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709460PMC
September 2019

Retrospective Identification of a Broad IgG Repertoire Differentiating Patients With Skin and Soft Tissue Infections From Controls.

Front Immunol 2019 7;10:114. Epub 2019 Feb 7.

Department of Medicine, University of Pennsylvania, Philadelphia, PA, United States.

Although the relevance of humoral immunity for protection against skin and soft tissue infections (SSTIs) has been suggested by several animal and human studies, the question of which human antibodies may be protective has so far impeded the development of a safe and effective vaccine. Because most adults have developed certain anti- antibodies due to colonization or infection, we hypothesized that the titers of antibodies to in uninfected controls would differ from those in infected patients and would also differ in infected patients from the time of acute infection to a 40-day convalescent serum. To test these hypotheses, we measured human antibody levels against a panel of 134 unique antigens comprising the surfome and secretome in subjects with active culture-confirmed SSTIs (cases) and in controls with no infection, using a novel protein microarray. Most SSTI patients ( = 60) and controls ( = 142) had antibodies to many of the tested antigens. Univariate analysis showed statistically weak differences in the IgG levels to some antigens in the SSTI patient (case) sera compared with controls. Antibody levels to most tested antigens did not increase comparing acute with 40-day serum. Multiple logistic regression identified a rich subset of antigens that, by their antibody levels, together correctly differentiated all cases from all controls. Antibodies directed against antigens were present both in patients with SSTIs and in uninfected control patients. We found that SSTI patients and controls could be distinguished only based on differences in antibody levels to many staphylococcal surface and secreted antigens. Our results demonstrate that in the studied population, the levels of anti- antibodies appear largely fixed, suggesting that there may be some level of unresponsiveness to natural infection.
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http://dx.doi.org/10.3389/fimmu.2019.00114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375365PMC
January 2020

Decreasing Incidence of Skin and Soft-tissue Infections in 86 US Emergency Departments, 2009-2014.

Clin Infect Dis 2019 01;68(3):453-459

Department of Public Health Sciences, University of Chicago, Illinois.

Background: The incidence of skin and soft-tissue infections (SSTIs), for which human immunodeficiency virus (HIV) is a significant risk factor, in United States emergency departments (EDs) increased dramatically after 2000 with the emergence of community-associated methicillin-resistant Staphylococcus aureus. Few studies have examined SSTI incidence among HIV-infected and non-HIV-infected patients in the United States after 2010.

Methods: Data were obtained for patient encounters at all academic medical center EDs affiliated with the Vizient clinical data warehouse assigned an SSTI-associated code based on the International Classification of Diseases, Ninth Revision, between 1 January 2009 and 31 December 2014. The rate was calculated per 1000 ED encounters by year and stratified by SSTI, HIV infection, or both, and by age group, race, payer type, and region of care. Poisson regression was used to assess temporal change over the study period.

Results: In 2009-2014, a total of 47317 HIV-associated and 820440 SSTI-associated encounters were recorded among 25239781 ED patient encounters. The rate of SSTIs decreased by 8% among all patients and by 14.6%, among those with HIV infection. The SSTI incidence overall decreased from 32.0 to 29.7 per 1000 ED encounters between 2009 and 2014. HIV-infected patients had a significantly higher rate of SSTIs than HIV-uninfected patients (adjusted rate ratio, 1.91; 95% confidence interval, 1.84-1.99).

Conclusions: The decline in SSTI incidence in US EDs between 2009 and 2014 is a remarkable epidemiologic shift from the increase in SSTIs after 2000, and further research is necessary to assess reasons for this decrease.
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http://dx.doi.org/10.1093/cid/ciy509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939314PMC
January 2019

Distinct T-helper cell responses to Staphylococcus aureus bacteremia reflect immunologic comorbidities and correlate with mortality.

Crit Care 2018 Apr 25;22(1):107. Epub 2018 Apr 25.

Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA.

Background: The dysregulated host immune response that defines sepsis varies as a function of both the immune status of the host and the distinct nature of the pathogen. The degree to which immunocompromising comorbidities or immunosuppressive medications affect the immune response to infection is poorly understood because these patients are often excluded from studies about septic immunity. The objectives of this study were to determine the immune response to a single pathogen (Staphylococcus aureus) among a diverse case mix of patients and to determine whether comorbidities affect immune and clinical outcomes.

Methods: Blood samples were drawn from 95 adult inpatients at multiple time points after the first positive S. aureus blood culture. Cox proportional hazards modeling was used to determine the associations between admission neutrophil counts, admission lymphocyte counts, cytokine levels, and 90-day mortality. A nested case-control flow cytometric analysis was conducted to determine T-helper type 1 (Th1), Th2, Th17, and regulatory T-cell (Treg) subsets among a subgroup of 28 patients. In a secondary analysis, we categorized patients as either having immunocompromising disorders (human immunodeficiency virus and hematologic malignancies), receiving immunosuppressive medications, or being not immunocompromised.

Results: Higher neutrophil-to-lymphocyte count ratios and higher Th17 cytokine responses relative to Th1 cytokine responses early after infection were independently associated with mortality and did not depend on the immune state of the patient (HR 1.93, 95% CI 1.17-3.17, p = 0.01; and HR 1.13, 95% CI 1.01-1.27, p = 0.03, respectively). On the basis of flow cytometric analysis of CD4 T-helper subsets, an increasing Th17/Treg response over the course of the infection was most strongly associated with increased mortality (HR 4.41, 95% CI 1.69-11.5, p < 0.01). This type of immune response was most common among patients who were not immunocompromised. In contrast, among immunocompromised patients who died, a decreasing Th1/Treg response was most common.

Conclusions: The association of both increased Th17 responses and increased neutrophil counts relative to lymphocyte counts with mortality suggests that an overwhelming inflammatory response is detrimental. However, the differential responses of patients according to immune state suggest that immune status is an important clinical indicator that should be accounted for in the management of septic patients, as well as in the development of novel immunomodulatory therapies.
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http://dx.doi.org/10.1186/s13054-018-2025-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5916828PMC
April 2018

A Trial of Antibiotics for Smaller Skin Abscesses.

N Engl J Med 2017 12;377(26):e36

University of California at San Francisco, San Francisco, CA

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http://dx.doi.org/10.1056/NEJMc1711124DOI Listing
December 2017

Metabolic Mitigation of Staphylococcus aureus Vancomycin Intermediate-Level Susceptibility.

Antimicrob Agents Chemother 2018 01 21;62(1). Epub 2017 Dec 21.

School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska, USA

is a major human pathogen whose infections are increasingly difficult to treat due to increased antibiotic resistance, including resistance to vancomycin. Vancomycin-intermediate (VISA) strains develop resistance to vancomycin through adaptive changes that are incompletely understood. Central to this adaptation are metabolic changes that permit growth in the presence of vancomycin. To define the metabolic changes associated with adaptive resistance to vancomycin in , the metabolomes of a vancomycin-sensitive and VISA strain pair isolated from the same patient shortly after vancomycin therapy began and following vancomycin treatment failure were analyzed. The metabolic adaptations included increases in acetogenesis, carbon flow through the pentose phosphate pathway, wall teichoic acid and peptidoglycan precursor biosynthesis, purine biosynthesis, and decreased tricarboxylic acid (TCA) cycle activity. The significance of these metabolic pathways for vancomycin-intermediate susceptibility was determined by assessing the synergistic potential of human-use-approved inhibitors of these pathways in combination with vancomycin against VISA strains. Importantly, inhibitors of amino sugar and purine biosynthesis acted synergistically with vancomycin to kill a diverse set of VISA strains, suggesting that combinatorial therapy could augment the efficacy of vancomycin even in patients infected with VISA strains.
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http://dx.doi.org/10.1128/AAC.01608-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5740343PMC
January 2018

Treatment of Staphylococcus aureus Infections.

Curr Top Microbiol Immunol 2017;409:325-383

Department of Pediatrics, The University of Chicago, 5841 S. Maryland Ave., MC6054, Chicago, IL, 60637, USA.

Staphylococcus aureus, although generally identified as a commensal, is also a common cause of human bacterial infections, including of the skin and other soft tissues, bones, bloodstream, and respiratory tract. The history of S. aureus treatment is marked by the development of resistance to each new class of antistaphylococcal antimicrobial drugs, including the penicillins, sulfonamides, tetracyclines, glycopeptides, and others, complicating therapy. S. aureus isolates identified in the 1960s were sometimes resistant to methicillin, a ß-lactam antimicrobial active initially against a majority S. aureus strains. These MRSA isolates, resistant to nearly all ß-lactam antimicrobials, were first largely confined to the health care environment and the patients who attended it. However, in the mid-1990s, new strains, known as community-associated (CA-) MRSA strains, emerged. CA-MRSA organisms, compared with health care-associated (HA-) MRSA strain types, are more often susceptible to multiple classes of non ß-lactam antimicrobials. While infections caused by methicillin-susceptible S. aureus (MSSA) strains are usually treated with drugs in the ß-lactam class, such as cephalosporins, oxacillin or nafcillin, MRSA infections are treated with drugs in other antimicrobial classes. The glycopeptide drug vancomycin, and in some countries teicoplanin, is the most common drug used to treat severe MRSA infections. There are now other classes of antimicrobials available to treat staphylococcal infections, including several that have been approved after 2009. The antimicrobial management of invasive and noninvasive S. aureus infections in the ambulatory and in-patient settings is the topic of this review. Also discussed are common adverse effects of antistaphylococcal antimicrobial agents, advantages of one agent over another for specific clinical syndromes, and the use of adjunctive therapies such as surgery and intravenous immunoglobulin. We have detailed considerations in the therapy of noninvasive and invasive S. aureus infections. This is followed by sections on specific clinical infectious syndromes including skin and soft tissue infections, bacteremia, endocarditis and intravascular infections, pneumonia, osteomyelitis and vertebral discitis, epidural abscess, septic arthritis, pyomyositis, mastitis, necrotizing fasciitis, orbital infections, endophthalmitis, parotitis, staphylococcal toxinoses, urogenital infections, and central nervous system infections.
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http://dx.doi.org/10.1007/82_2017_42DOI Listing
May 2019

Decreasing Incidence of Skin and Soft Tissue Infections With a Seasonal Pattern at an Academic Medical Center, 2006-2014.

Open Forum Infect Dis 2016 Oct 30;3(4):ofw179. Epub 2016 Aug 30.

Departments of Public Health Sciences.

 The incidence of skin and soft tissue infections (SSTIs) in the United States increased sharply after 2000 with the emergence of USA300 methicillin-resistant . We examined trends in SSTI incidence in 2006-2014 at the University of Chicago Medicine (UCM).  Data were obtained for patient encounters at UCM with an -coded SSTI diagnosis between January 1, 2006 and March 31, 2014. Incidence density was calculated per 1000 encounters by quarter and year. Encounters were stratified by inpatient, outpatient clinic and emergency department (ED) encounters and by age group, gender, and race. Poisson regression was used to assess change over time.  In 2006-2014, data were collected for 38 201 SSTI-associated encounters among 31 869 subjects. Among all patients treated at UCM, there was a decrease of 1% per year in the incidence of SSTIs during 2006-2013, with an overall decrease of 16%. There was a significant decrease in SSTI-related encounters among inpatients (rate ratio [RR] = 0.97; 95% confidence interval [CI], .96-.98), ED patients (RR = 0.98; 95% CI, .97-.98), adults (RR = 0.98; 95% CI, .97-.98), children (RR = 0.96; 95% CI, .95-.97), and African Americans (RR = 0.99; 95% CI, .98-.99). There was an annual seasonal trend, with the peak incidence occurring during the late summer.  The incidence of SSTIs at UCM decreased in children and adults with seasonal variation, peaking during the summer months. This suggests a reversal of the massive increase in SSTI incidence in the United States after 2000.
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http://dx.doi.org/10.1093/ofid/ofw179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5063547PMC
October 2016

A Placebo-Controlled Trial of Antibiotics for Smaller Skin Abscesses.

N Engl J Med 2017 06;376(26):2545-2555

From the University of Chicago Hospitals, Chicago (R.S.D., N.K.); Harbor-UCLA Medical Center and Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Los Angeles (L.G.M., S.J.E.), and University of California, San Francisco-San Francisco General Hospital, San Francisco (D.Y., M.D., H.F.C.); Morehouse School of Medicine and Emory University-Grady Memorial Hospital and Children's Healthcare of Atlanta, Atlanta (L.I., T.C.P.); Washington University School of Medicine-Barnes-Jewish Hospital and St. Louis Children's Hospital, St. Louis (S.F., M.G.B.); Vanderbilt University School of Medicine and Vanderbilt University Medical Center, Nashville (C.B.C.); EMMES Corporation, Rockville, MD (S.P.); and Cota Enterprises, Meriden, KS (R.H.).

Background: Uncomplicated skin abscesses are common, yet the appropriate management of the condition in the era of community-associated methicillin-resistant Staphylococcus aureus (MRSA) is unclear.

Methods: We conducted a multicenter, prospective, double-blind trial involving outpatient adults and children. Patients were stratified according to the presence of a surgically drainable abscess, abscess size, the number of sites of skin infection, and the presence of nonpurulent cellulitis. Participants with a skin abscess 5 cm or smaller in diameter were enrolled. After abscess incision and drainage, participants were randomly assigned to receive clindamycin, trimethoprim-sulfamethoxazole (TMP-SMX), or placebo for 10 days. The primary outcome was clinical cure 7 to 10 days after the end of treatment.

Results: We enrolled 786 participants: 505 (64.2%) were adults and 281 (35.8%) were children. A total of 448 (57.0%) of the participants were male. S. aureus was isolated from 527 participants (67.0%), and MRSA was isolated from 388 (49.4%). Ten days after therapy in the intention-to-treat population, the cure rate among participants in the clindamycin group was similar to that in the TMP-SMX group (221 of 266 participants [83.1%] and 215 of 263 participants [81.7%], respectively; P=0.73), and the cure rate in each active-treatment group was higher than that in the placebo group (177 of 257 participants [68.9%], P<0.001 for both comparisons). The results in the population of patients who could be evaluated were similar. This beneficial effect was restricted to participants with S. aureus infection. Among the participants who were initially cured, new infections at 1 month of follow-up were less common in the clindamycin group (15 of 221, 6.8%) than in the TMP-SMX group (29 of 215 [13.5%], P=0.03) or the placebo group (22 of 177 [12.4%], P=0.06). Adverse events were more frequent with clindamycin (58 of 265 [21.9%]) than with TMP-SMX (29 of 261 [11.1%]) or placebo (32 of 255 [12.5%]); all adverse events resolved without sequelae. One participant who received TMP-SMX had a hypersensitivity reaction.

Conclusions: As compared with incision and drainage alone, clindamycin or TMP-SMX in conjunction with incision and drainage improves short-term outcomes in patients who have a simple abscess. This benefit must be weighed against the known side-effect profile of these antimicrobials. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00730028 .).
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http://dx.doi.org/10.1056/NEJMoa1607033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886470PMC
June 2017

Evaluation of serotypes 5 and 8 capsular polysaccharides in protection against Staphylococcus aureus in murine models of infection.

Hum Vaccin Immunother 2017 07 19;13(7):1609-1614. Epub 2017 Apr 19.

c Department of Pediatrics , University of Chicago , Chicago , IL , USA.

Staphylococcus aureus is the leading cause of nosocomial and community-acquired infections, including soft tissue and skin infections and bacteremia. However, efforts to develop an effective vaccine against S. aureus infections have not been successful. We evaluated serotypes 5 and 8 capsule polysaccharides (CP) CRM conjugates as vaccine candidates in murine models of bacteremia, lethal sepsis, and skin infection. The conjugate vaccines elicited a good antibody response, and active immunization of CP5-CRM or CP8-CRM conjugates protected against staphylococcal bacteremia. In the skin infection model, CP8-CRM but not CP5-CRM protected against dermonecrosis, and CP8-CRM immunization significantly decreased the bacterial burden in the lesion. However, neither CP5-CRM nor CP8-CRM protected against mortality in the lethal sepsis model. The results indicate the capsular vaccines elicit protection against some, but not all, aspects of staphylococcal infection.
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http://dx.doi.org/10.1080/21645515.2017.1304334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5512765PMC
July 2017

Daptomycin for Complicated Skin Infections: A Randomized Trial.

Pediatrics 2017 Mar 15;139(3). Epub 2017 Feb 15.

Merck & Co, Inc, Kenilworth, New Jersey.

Background: Complicated skin and skin structure infections (cSSSI) are common in children. Due to safety and resistance issues with recommended agents, new treatment options would be advantageous.

Methods: Multicenter, evaluator-blinded clinical trial. Patients 1 to 17 years old with cSSSI caused by Gram-positive pathogens were randomized 2:1 to intravenous daptomycin or standard-of-care (SOC) treatment for ≤14 days. Daptomycin was administered once daily with dosing by patient age: 12 to 17 years, 5 mg/kg; 7 to 11 years, 7 mg/kg; 2 to 6 years, 9 mg/kg; 12 to 23 months, 10 mg/kg. The primary objective was to evaluate daptomycin safety. The secondary objective was to assess the efficacy of daptomycin compared with SOC. The intent-to-treat (ITT) population consisted of all randomized patients with any dose of study drug.

Results: The ITT population comprised 257 daptomycin and 132 SOC patients (primarily clindamycin or vancomycin); 35% had confirmed methicillin-resistant . The most common adverse events were diarrhea (7% daptomycin, 5% SOC) and increased creatine phosphokinase (6% daptomycin, 5% SOC). The proportions of safety population patients with treatment-related adverse events were similar between the daptomycin (14%) and SOC (17%) groups. Clinical success rates (blinded evaluator-assessed complete/partial resolution of cSSSI signs and symptoms 7-14 days after end-of-treatment) in the ITT population were also similar for the daptomycin (91%) and SOC groups.

Conclusions: Once-daily daptomycin was well tolerated, with safety and efficacy comparable to SOC in children/adolescents with cSSSI caused by Gram-positive pathogens, including community-acquired methicillin-resistant .
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http://dx.doi.org/10.1542/peds.2016-2477DOI Listing
March 2017

Can Methicillin-resistant Staphylococcus aureus Silently Travel From the Gut to the Wound and Cause Postoperative Infection? Modeling the "Trojan Horse Hypothesis".

Ann Surg 2018 04;267(4):749-758

Center for Surgical Infection Research and Therapeutics, Pritzker School of Medicine, University of Chicago, Chicago, IL.

Objective: To determine whether intestinal colonization with methicillin-resistant Staphylococcus aureus (MRSA) can be the source of surgical site infections (SSIs).

Background: We hypothesized that gut-derived MRSA may cause SSIs via mechanisms in which circulating immune cells scavenge MRSA from the gut, home to surgical wounds, and cause infection (Trojan Horse Hypothesis).

Methods: MRSA gut colonization was achieved by disrupting the microbiota with antibiotics, imposing a period of starvation and introducing MRSA via gavage. Next, mice were subjected to a surgical injury (30% hepatectomy) and rectus muscle injury and ischemia before skin closure. All wounds were cultured before skin closure. To control for postoperative wound contamination, reiterative experiments were performed in mice in which the closed wound was painted with live MRSA for 2 consecutive postoperative days. To rule out extracellular bacteremia as a cause of wound infection, MRSA was injected intravenously in mice subjected to rectus muscle ischemia and injury.

Results: All wound cultures were negative before skin closure, ruling out intraoperative contamination. Out of 40 mice, 4 (10%) developed visible abscesses. Nine mice (22.5%) had MRSA positive cultures of the rectus muscle without visible abscesses. No SSIs were observed in mice injected intravenously with MRSA. Wounds painted with MRSA after closure did not develop infections. Circulating neutrophils from mice captured by flow cytometry demonstrated MRSA in their cytoplasm.

Conclusions: Immune cells as Trojan horses carrying gut-derived MRSA may be a plausible mechanism of SSIs in the absence of direct contamination.
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http://dx.doi.org/10.1097/SLA.0000000000002173DOI Listing
April 2018

Identification of source and sink populations for the emergence and global spread of the East-Asia clone of community-associated MRSA.

Genome Biol 2016 07 26;17(1):160. Epub 2016 Jul 26.

The Roslin Institute, University of Edinburgh, Edinburgh, UK.

Background: Our understanding of the factors influencing the emergence, dissemination and global distribution of epidemic clones of bacteria is limited. ST59 is a major epidemic clone of community-associated MRSA in East Asia, responsible for extensive morbidity and mortality, but has a much lower prevalence in other parts of the world. The geographic origin of ST59 and its international routes of dissemination are unclear and disputed in the literature.

Results: To investigate the origin and spread of the ST59 clone, we obtained whole genome sequences of isolates from four continents, sampled over more than a decade, and carried out a time-scaled phylogeographic analysis. We discover that two distinct ST59 clades emerged concurrently, in East Asia and the USA, but underwent clonal expansion at different times. The East Asia clade was strongly enriched for gene determinants associated with antibiotic resistance, consistent with regional differences in antibiotic usage. Both clones spread independently to Australia and Europe, and we found evidence of the persistence of multi-drug resistance following export from East Asia. Direct transfer of strains between Taiwan and the USA was not observed in either direction, consistent with geographic niche exclusion.

Conclusions: Our results resolve a longstanding controversy regarding the origin of the ST59 clone, revealing the major global source and sink populations and routes for the spread of multi-drug resistant clones. Additionally, our findings indicate that diversification of the accessory genome of epidemic clones partly reflects region-specific patterns of antibiotic usage, which may influence bacterial fitness after transmission to different geographic locations.
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http://dx.doi.org/10.1186/s13059-016-1022-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4962458PMC
July 2016

Impact of Staphylococcus aureus USA300 Colonization and Skin Infections on Systemic Immune Responses in Humans.

J Immunol 2016 08 11;197(4):1118-26. Epub 2016 Jul 11.

Department of Pediatrics, University of Chicago, Chicago, IL 60637; Department of Surgery, University of Chicago, Chicago, IL 60637.

Staphylococcus aureus is both a commensal and a pathogen, and USA300, a strain that is usually methicillin-resistant but can sometimes be methicillin-susceptible, has been causing skin and soft tissue infections (SSTIs) in epidemic proportions among otherwise healthy individuals. Although many people are colonized with S. aureus strains, including some with USA300, few of these colonized individuals develop SSTIs. This prompts the hypothesis that infections may develop in individuals with somewhat reduced innate and/or adaptive immune responses to S. aureus, either because prior S. aureus colonization has dampened such responses selectively, or because of more globally reduced immune reactivity. In this study, we analyzed the S. aureus colonization status and PBMC responses to innate and adaptive stimuli in 72 patients with SSTIs and 143 uninfected demographically matched controls. Contrary to the hypothesis formulated, PBMCs from infected patients obtained at the time of infection displayed enhanced innate cytokine production upon restimulation compared with PBMCs from controls, a difference that disappeared after infection resolution. Notably, PBMCs from patients infected with a documented USA300 SSTI displayed greater innate cytokine production than did those from patients infected with documented non-USA300 genotypes. Moreover, colonization with USA300 in infected patients, regardless of their infecting strain, correlated with increased production of IL-10, IL-17A, and IL-22 compared with patients colonized with non-USA300 subtypes. Thus, our results demonstrate that infected patients associated with USA300 either as an infecting strain, or as a colonizing strain, have systemic immune responses of greater magnitude than do those associated with other S. aureus subtypes.
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http://dx.doi.org/10.4049/jimmunol.1600549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4976020PMC
August 2016

Intrahost Evolution of Methicillin-Resistant Staphylococcus aureus USA300 Among Individuals With Reoccurring Skin and Soft-Tissue Infections.

J Infect Dis 2016 09 10;214(6):895-905. Epub 2016 Jun 10.

Department of Pediatrics Department of Medicine, University of Chicago, Illinois.

Background: Methicillin-resistant Staphylococcus aureus (MRSA) USA300 is the leading cause of MRSA infections in the United States and has caused an epidemic of skin and soft-tissue infections. Recurrent infections with USA300 MRSA are common, yet intrahost evolution during persistence on an individual has not been studied. This gap hinders the ability to clinically manage recurrent infections and reconstruct transmission networks.

Methods: To characterize bacterial intrahost evolution, we examined the clinical courses of 4 subjects with 3-6 recurrent USA300 MRSA infections, using patient clinical data, including antibiotic exposure history, and whole-genome sequencing and phylogenetic analysis of all available MRSA isolates (n = 29).

Results: Among sequential isolates, we found variability in diversity, accumulation of mutations, and mobile genetic elements. Selection for antimicrobial-resistant populations was observed through both an increase in the number of plasmids conferring multidrug resistance and strain replacement by a resistant population. Two of 4 subjects had strain replacement with a genetically distinct USA300 MRSA population.

Discussions: During a 5-year period in 4 subjects, we identified development of antimicrobial resistance, intrahost evolution, and strain replacement among isolates from patients with recurrent MRSA infections. This calls into question the efficacy of decolonization to prevent recurrent infections and highlights the adaptive potential of USA300 and the need for effective sampling.
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http://dx.doi.org/10.1093/infdis/jiw242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996148PMC
September 2016

CLINICAL DECISIONS. Skin Abscess.

N Engl J Med 2016 Mar;374(9):882-4

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http://dx.doi.org/10.1056/NEJMclde1600286DOI Listing
March 2016

Proteomic Identification of saeRS-Dependent Targets Critical for Protective Humoral Immunity against Staphylococcus aureus Skin Infection.

Infect Immun 2015 Sep 13;83(9):3712-21. Epub 2015 Jul 13.

Department of Pediatrics, University of Chicago, Chicago, Illinois, USA

Recurrent Staphylococcus aureus skin and soft tissue infections (SSTIs) are common despite detectable antibody responses, leading to the belief that the immune response elicited by these infections is not protective. We recently reported that S. aureus USA300 SSTI elicits antibodies that protect against recurrent SSTI in BALB/c but not C57BL/6 mice, and in this study, we aimed to uncover the specificity of the protective antibodies. Using a proteomic approach, we found that S. aureus SSTI elicited broad polyclonal antibody responses in both BALB/c and C57BL/6 mice and identified 10 S. aureus antigens against which antibody levels were significantly higher in immune BALB/c serum. Four of the 10 antigens identified are regulated by the saeRS operon, suggesting a dominant role for saeRS in protection. Indeed, infection with USA300Δsae failed to protect against secondary SSTI with USA300, despite eliciting a strong polyclonal antibody response against antigens whose expression is not regulated by saeRS. Moreover, the antibody repertoire after infection with USA300Δsae lacked antibodies specific for 10 saeRS-regulated antigens, suggesting that all or a subset of these antigens are necessary to elicit protective immunity. Infection with USA300Δhla elicited modest protection against secondary SSTI, and complementation of USA300Δsae with hla restored protection but incompletely. Together, these findings support a role for both Hla and other saeRS-regulated antigens in eliciting protection and suggest that host differences in immune responses to saeRS-regulated antigens may determine whether S. aureus infection elicits protective or nonprotective immunity against recurrent infection.
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http://dx.doi.org/10.1128/IAI.00667-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4534640PMC
September 2015

Pediatric Staphylococcus aureus Isolate Genotypes and Infections from the Dawn of the Community-Associated Methicillin-Resistant S. aureus Epidemic Era in Chicago, 1994 to 1997.

J Clin Microbiol 2015 Aug 27;53(8):2486-91. Epub 2015 May 27.

Department of Pediatrics, University of Chicago, Chicago, Illinois, USA.

Widespread infections with community-associated (CA) methicillin-resistant Staphylococcus aureus (MRSA) have occurred in the United States with the dissemination of the USA300 strain beginning in 2000. We examined 105 isolates obtained from children treated at the University of Chicago from 1994 to 1997 (75 methicillin-susceptible S. aureus [MSSA] and 30 MRSA isolates) in order to investigate for possible evidence of USA300 during this period. Infections were defined epidemiologically based on medical record review. The isolates underwent multilocus sequence typing (MLST), as well as assays for the Panton-Valentine leukocidin (PVL) genes, the protein A gene (spa), and arcA and opp3, proxy markers for the arginine catabolic mobile element (ACME), characteristic of USA300 MRSA. MRSA isolates also underwent staphylococcal cassette chromosome mec (SCCmec) typing and pulsed-field gel electrophoresis (PFGE) subtyping. MSSA isolates belonged to 17 sequence type (ST) groups. The 12 epidemiologically defined CA-MRSA infection isolates were either ST1 (n = 4) or ST8 (n = 8). They belonged to 3 different PFGE types: USA100 (n = 1), USA400 (n = 5), and USA500 (n = 6). Among the CA-MRSA infection isolates, 8 (67%) were PVL(+). None of the MRSA or MSSA isolates contained arcA or opp3. Only one MRSA isolate was USA300 by PFGE. This was a health care-associated (HA) MRSA isolate, negative for PVL, that carried SCCmec type II. USA300 with its characteristic features was not identified in the collection from the years 1994 to 1997.
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http://dx.doi.org/10.1128/JCM.00096-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4508449PMC
August 2015

Staphylococcus aureus metabolic adaptations during the transition from a daptomycin susceptibility phenotype to a daptomycin nonsusceptibility phenotype.

Antimicrob Agents Chemother 2015 Jul 11;59(7):4226-38. Epub 2015 May 11.

School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska, USA

Staphylococcus aureus is a major cause of nosocomial and community-acquired infections. The success of S. aureus as a pathogen is due in part to its many virulence determinants and resistance to antimicrobials. In particular, methicillin-resistant S. aureus has emerged as a major cause of infections and led to increased use of the antibiotics vancomycin and daptomycin, which has increased the isolation of vancomycin-intermediate S. aureus and daptomycin-nonsusceptible S. aureus strains. The most common mechanism by which S. aureus acquires intermediate resistance to antibiotics is by adapting its physiology and metabolism to permit growth in the presence of these antibiotics, a process known as adaptive resistance. To better understand the physiological and metabolic changes associated with adaptive resistance, six daptomycin-susceptible and -nonsusceptible isogenic strain pairs were examined for changes in growth, competitive fitness, and metabolic alterations. Interestingly, daptomycin nonsusceptibility coincides with a slightly delayed transition to the postexponential growth phase and alterations in metabolism. Specifically, daptomycin-nonsusceptible strains have decreased tricarboxylic acid cycle activity, which correlates with increased synthesis of pyrimidines and purines and increased carbon flow to pathways associated with wall teichoic acid and peptidoglycan biosynthesis. Importantly, these data provided an opportunity to alter the daptomycin nonsusceptibility phenotype by manipulating bacterial metabolism, a first step in developing compounds that target metabolic pathways that can be used in combination with daptomycin to reduce treatment failures.
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http://dx.doi.org/10.1128/AAC.00160-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468685PMC
July 2015

Host factors that contribute to recurrent staphylococcal skin infection.

Curr Opin Infect Dis 2015 Jun;28(3):253-8

aSections of Critical Care bInfectious Diseases, Department of Pediatrics cSection of Infectious Diseases and Global Health, Department of Medicine, University of Chicago, Chicago, Illinois, USA.

Purpose Of Review: Staphylococcus aureus is the most common cause of skin and soft tissue infections (SSTI) in the United States and elsewhere. Recurrent infections occur frequently in patients with S. aureus SSTI, underscoring the need to better understand the nature of protective immunity against these infections. Here, we review recent findings concerning the host factors that predispose to S. aureus SSTI.

Recent Findings: Recurrent infections occur in nearly half of all patients with S. aureus SSTI. Epidemiologic and environmental factors, such as exposure to healthcare, age, and household contacts with S. aureus SSTI, and contaminated household fomites are associated with recurrence. The majority of the population has evidence of antistaphylococcal antibodies, but whether these are protective remains enigmatic. In contrast, recent clinical and experimental findings clearly highlight the critical roles of innate and T cell-mediated immunity in defense against these infections. S. aureus interferes with innate and adaptive immunity by a number of recently elucidated mechanisms.

Summary: Recurrent S. aureus SSTIs are common, suggesting incomplete or absent protective immunity among these patients. Our understanding of protective immunity against recurrent infections is incomplete, and further basic and translational investigation is urgently needed to design strategies to prevent and treat these infections.
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http://dx.doi.org/10.1097/QCO.0000000000000156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414914PMC
June 2015

USA300 and USA500 clonal lineages of Staphylococcus aureus do not produce a capsular polysaccharide due to conserved mutations in the cap5 locus.

mBio 2015 Apr 7;6(2). Epub 2015 Apr 7.

Department of Pediatrics, Section of Infectious Diseases, The University of Chicago, Chicago, Illinois, USA.

Unlabelled: The surface capsular polysaccharide (CP) is a virulence factor that has been used as an antigen in several successful vaccines against bacterial pathogens. A vaccine has not yet been licensed against Staphylococcus aureus, although two multicomponent vaccines that contain CP antigens are in clinical trials. In this study, we evaluated CP production in USA300 methicillin-resistant S. aureus (MRSA) isolates that have become the predominant community-associated MRSA clones in the United States. We found that all 167 USA300 MRSA and 50 USA300 methicillin-susceptible S. aureus (MSSA) isolates were CP negative (CP(-)). Moreover, all 16 USA500 isolates, which have been postulated to be the progenitor lineage of USA300, were also CP(-). Whole-genome sequence analysis of 146 CP(-) USA300 MRSA isolates revealed they all carry a cap5 locus with 4 conserved mutations compared with strain Newman. Genetic complementation experiments revealed that three of these mutations (in the cap5 promoter, cap5D nucleotide 994, and cap5E nucleotide 223) ablated CP production in USA300 and that Cap5E75 Asp, located in the coenzyme-binding domain, is essential for capsule production. All but three USA300 MSSA isolates had the same four cap5 mutations found in USA300 MRSA isolates. Most isolates with a USA500 pulsotype carried three of these four USA300-specific mutations, suggesting the fourth mutation occurred in the USA300 lineage. Phylogenetic analysis of the cap loci of our USA300 isolates as well as publicly available genomes from 41 other sequence types revealed that the USA300-specific cap5 mutations arose sequentially in S. aureus in a common ancestor of USA300 and USA500 isolates.

Importance: The USA300 MRSA clone emerged as a community-associated pathogen in the United States nearly 20 years ago. Since then, it has rapidly disseminated and now causes health care-associated infections. This study shows that the CP-negative (CP(-)) phenotype has persisted among USA300 isolates and is a universal and characteristic trait of this highly successful MRSA lineage. It is important to note that a vaccine consisting solely of CP antigens would not likely demonstrate high efficacy in the U.S. population, where about half of MRSA isolates comprise USA300. Moreover, conversion of a USA300 strain to a CP-positive (CP(+)) phenotype is unlikely in vivo or in vitro since it would require the reversion of 3 mutations. We have also established that USA300 MSSA isolates and USA500 isolates are CP(-) and provide new insight into the evolution of the USA300 and USA500 lineages.
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http://dx.doi.org/10.1128/mBio.02585-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4453534PMC
April 2015

Clindamycin versus trimethoprim-sulfamethoxazole for uncomplicated skin infections.

N Engl J Med 2015 Mar;372(12):1093-103

From the Los Angeles Biomedical Research Institute (L.G.M., S.J.E.) and Division of Infectious Diseases, Harbor-UCLA (University of California, Los Angeles) Medical Center (L.G.M., S.J.E.), Torrance, David Geffen School of Medicine at UCLA, Los Angeles (L.G.M., S.J.E.), Division of Plastic and Reconstructive Surgery, University of California, San Francisco (UCSF) (D.Y.), and Division of Infectious Diseases, San Francisco General Hospital and UCSF (M.D.D., H.F.C.), San Francisco - all in California; Division of Pediatric Infectious Diseases, University of Chicago, Chicago (R.S.D.); Division of Pediatric Infectious Diseases, Vanderbilt University, Nashville (C.B.C.); the EMMES Corporation, Rockville, MD (S.P.); and Cota Enterprises, Meriden, KS (R.J.H.).

Background: Skin and skin-structure infections are common in ambulatory settings. However, the efficacy of various antibiotic regimens in the era of community-acquired methicillin-resistant Staphylococcus aureus (MRSA) is unclear.

Methods: We enrolled outpatients with uncomplicated skin infections who had cellulitis, abscesses larger than 5 cm in diameter (smaller for younger children), or both. Patients were enrolled at four study sites. All abscesses underwent incision and drainage. Patients were randomly assigned in a 1:1 ratio to receive either clindamycin or trimethoprim-sulfamethoxazole (TMP-SMX) for 10 days. Patients and investigators were unaware of the treatment assignments and microbiologic test results. The primary outcome was clinical cure 7 to 10 days after the end of treatment.

Results: A total of 524 patients were enrolled (264 in the clindamycin group and 260 in the TMP-SMX group), including 155 children (29.6%). One hundred sixty patients (30.5%) had an abscess, 280 (53.4%) had cellulitis, and 82 (15.6%) had mixed infection, defined as at least one abscess lesion and one cellulitis lesion. S. aureus was isolated from the lesions of 217 patients (41.4%); the isolates in 167 (77.0%) of these patients were MRSA. The proportion of patients cured was similar in the two treatment groups in the intention-to-treat population (80.3% in the clindamycin group and 77.7% in the TMP-SMX group; difference, -2.6 percentage points; 95% confidence interval [CI], -10.2 to 4.9; P=0.52) and in the populations of patients who could be evaluated (466 patients; 89.5% in the clindamycin group and 88.2% in the TMP-SMX group; difference, -1.2 percentage points; 95% CI, -7.6 to 5.1; P=0.77). Cure rates did not differ significantly between the two treatments in the subgroups of children, adults, and patients with abscess versus cellulitis. The proportion of patients with adverse events was similar in the two groups.

Conclusions: We found no significant difference between clindamycin and TMP-SMX, with respect to either efficacy or side-effect profile, for the treatment of uncomplicated skin infections, including both cellulitis and abscesses. (Funded by the National Institute of Allergy and Infectious Diseases and the National Center for Advancing Translational Sciences, National Institutes of Health; ClinicalTrials.gov number, NCT00730028.).
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http://dx.doi.org/10.1056/NEJMoa1403789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4547538PMC
March 2015

Transmission and microevolution of USA300 MRSA in U.S. households: evidence from whole-genome sequencing.

mBio 2015 Mar 10;6(2):e00054. Epub 2015 Mar 10.

Unlabelled: Methicillin-resistant Staphylococcus aureus (MRSA) USA300 is a successful S. aureus clone in the United States and a common cause of skin and soft tissue infections (SSTIs). We performed whole-genome sequencing (WGS) of 146 USA300 MRSA isolates from SSTIs and colonization cultures obtained from an investigation conducted from 2008 to 2010 in Chicago and Los Angeles households that included an index case with an S. aureus SSTI. Identifying unique single nucleotide polymorphisms (SNPs) and analyzing whole-genome phylogeny, we characterized isolates to understand transmission dynamics, genetic relatedness, and microevolution of USA300 MRSA within the households. We also compared the 146 USA300 MRSA isolates from our study with the previously published genome sequences of the USA300 MRSA isolates from San Diego (n = 35) and New York City (n = 277). We found little genetic variation within the USA300 MRSA household isolates from Los Angeles (mean number of SNPs ± standard deviation, 17.6 ± 35; π nucleotide diversity, 3.1 × 10(-5)) or from Chicago (mean number of SNPs ± standard deviation, 12 ± 19; π nucleotide diversity, 3.1 × 10(-5)). The isolates within a household clustered into closely related monophyletic groups, suggesting the introduction into and transmission within each household of a single common USA300 ancestral strain. From a Bayesian evolutionary reconstruction, we inferred that USA300 persisted within households for 2.33 to 8.35 years prior to sampling. We also noted that fluoroquinolone-resistant USA300 clones emerged around 1995 and were more widespread in Los Angeles and New York City than in Chicago. Our findings strongly suggest that unique USA300 MRSA isolates are transmitted within households that contain an individual with an SSTI. Decolonization of household members may be a critical component of prevention programs to control USA300 MRSA spread in the United States.

Importance: USA300, a virulent and easily transmissible strain of methicillin-resistant Staphylococcus aureus (MRSA), is the predominant community-associated MRSA clone in the United States. It most commonly causes skin infections but also causes necrotizing pneumonia and endocarditis. Strategies to limit the spread of MRSA in the community can only be effective if we understand the most common sources of transmission and the microevolutionary processes that provide a fitness advantage to MRSA. We performed a whole-genome sequence comparison of 146 USA300 MRSA isolates from Chicago and Los Angeles. We show that households represent a frequent site of transmission and a long-term reservoir of USA300 strains; individuals within households transmit the same USA300 strain among themselves. Our study also reveals that a large proportion of the USA300 isolates sequenced are resistant to fluoroquinolone antibiotics. The significance of this study is that if households serve as long-term reservoirs of USA300, household MRSA eradication programs may result in a uniquely effective control method.
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http://dx.doi.org/10.1128/mBio.00054-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4453535PMC
March 2015

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 24;53(3):810-5. Epub 2014 Dec 24.

University of Chicago, Section of Infectious Diseases, Department of Pediatrics, Chicago, Illinois, USA

Staphylococcus aureus is a commensal species that can also be a formidable pathogen. In the United States, an epidemic of community-acquired methicillin-resistant Staphylococcus aureus (MRSA) infections has been occurring for the last 15 years. In the context of a study in which we identified patients with skin and soft tissue infections (SSTIs) and randomized them to receive one of two antimicrobial treatment regimens, we assessed S. aureus colonization in the nares, throat, and perianal skin on the day of enrollment and 40 days after therapy. We compared the prevalence of colonization between the SSTI patients and an uninfected control population. A total of 144 subjects and 130 controls, predominantly African American, participated in this study, and 116 returned for a 40-day follow-up visit. Of the SSTI patients, 76% were colonized with S. aureus at enrollment, as were 65% of the controls. Patients were more likely than the controls to be colonized with USA300 MRSA (62/144 [43.1%] versus 11/130 [8.5%], respectively; P < 0.001). The nares were not the most common site of colonization. The colonization prevalence diminished somewhat after antibiotic treatment but remained high. The isolates that colonized the controls were more likely than those in the patients to be methicillin-susceptible S. aureus (MSSA) (74/84 [88.1%] versus 56/106 [52.8%], respectively; P < 0.001). In conclusion, the prevalence of S. aureus colonization among SSTI patients was high and often involved USA300 MRSA. The prevalence diminished somewhat with antimicrobial therapy but remained high at the 40-day follow-up visit. Control subjects were also colonized at a high prevalence but most often with a genetic background not associated with a clinical infection in this study. S. aureus is a commensal species and a pathogen. Plans for decolonization or eradication should take this distinction into account.
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http://dx.doi.org/10.1128/JCM.03221-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4390638PMC
March 2015

Genomic and transcriptomic differences in community acquired methicillin resistant Staphylococcus aureus USA300 and USA400 strains.

BMC Genomics 2014 Dec 19;15:1145. Epub 2014 Dec 19.

Department of Pediatrics, Section of Critical Care, University of Chicago, Chicago, IL, 60637, USA.

Background: Staphylococcus aureus is a human pathogen responsible for substantial morbidity and mortality through its ability to cause a number of human infections including bacteremia, pneumonia and soft tissue infections. Of great concern is the emergence and dissemination of methicillin-resistant Staphylococcus aureus strains (MRSA) that are resistant to nearly all β-lactams. The emergence of the USA300 MRSA genetic background among community associated S. aureus infections (CA-MRSA) in the USA was followed by the disappearance of USA400 CA-MRSA isolates.

Results: To gain a greater understanding of the potential fitness advantages and virulence capacity of S. aureus USA300 clones, we performed whole genome sequencing of 15 USA300 and 4 USA400 clinical isolates. A comparison of representative genomes of the USA300 and USA400 pulsotypes indicates a number of differences in mobile genome elements. We examined the in vitro gene expression profiles by microarray hybridization and the in vivo transcriptomes during lung infection in mice of a USA300 and a USA400 MRSA strain by performing complete genome qRT-PCR analysis. The unique presence and increased expression of 6 exotoxins in USA300 (12- to 600-fold) compared to USA400 may contribute to the increased virulence of USA300 clones. Importantly, we also observed the up-regulation of prophage genes in USA300 (compared with USA400) during mouse lung infection (including genes encoded by both prophages ΦSa2usa and ΦSa3usa), suggesting that these prophages may play an important role in vivo by contributing to the elevated virulence characteristic of the USA300 clone.

Conclusions: We observed differences in the genetic content of USA300 and USA400 strains, as well as significant differences of in vitro and in vivo gene expression of mobile elements in a lung pneumonia model. This is the first study to document the global transcription differences between USA300 and USA400 strains during both in vitro and in vivo growth.
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http://dx.doi.org/10.1186/1471-2164-15-1145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630920PMC
December 2014

Staphylococcus aureus skin infection recurrences among household members: an examination of host, behavioral, and pathogen-level predictors.

Clin Infect Dis 2015 Mar 26;60(5):753-63. Epub 2014 Nov 26.

Section of Infectious Diseases, Department of Pediatrics, University of Chicago, Illinois.

Background: Many patients suffer from recurrent Staphylococcus aureus infections, but there are few data examining recurrence predictors.

Methods: We followed adults and children after treatment for S. aureus skin infections and their household contacts in Los Angeles and Chicago. We surveyed subjects for S. aureus body colonization, household fomite contamination, and behavioral and clinical factors at baseline and 3 and 6 months later. Using repeated measures modeling, we examined host, pathogen, behavioral, and clinical factors associated with recurrence.

Results: Among 330 index subjects, 182 (55%) were infected with an isolate of the USA300 methicillin-resistant S. aureus (MRSA) genetic background. Recurrences occurred in 39% by month 3 and 51% by month 6. Among 588 household contacts, 10% reported a skin infection by month 3 and 13% by month 6. Among index subjects, recurrence was associated with (P < .05) Los Angeles site, diabetes, recent hospitalization, recent skin infection, recent cephalexin use, and household S. aureus or MRSA fomite contamination; recurrence was inversely associated with recent contact sports participation. In the multivariate model, independent predictors of recurrence in index patients were recent hospitalization, household MRSA fomite contamination, and lack of recent contact sports participation. Among household contacts, independent predictors of subsequent skin infection were Chicago site, antibiotic use in the prior year, and skin infection in the prior 3 months.

Conclusions: In our longitudinal study, patients with a S. aureus skin infection were more likely to suffer a recurrence if household fomites were MRSA contaminated. Interventions to prevent recurrence may be enhanced by decontamination of household fomites.
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http://dx.doi.org/10.1093/cid/ciu943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4402346PMC
March 2015

A randomized, controlled trial of chlorhexidine-soaked cloths to reduce methicillin-resistant and methicillin-susceptible Staphylococcus aureus carriage prevalence in an urban jail.

Infect Control Hosp Epidemiol 2014 Dec;35(12):1466-73

Department of Medicine, University of Chicago, Chicago, Illinois.

Objective: To assess an intervention to limit community-associated methicillin-resistant Staphylococcus aureus (MRSA) dissemination.

Design: Randomized, controlled trial.

Setting: County Jail, Dallas, Texas.

Participants: A total of 4,196 detainees in 68 detention tanks.

Methods: Tanks were randomly assigned to 1 of 3 groups: in group 1, detainees received cloths that contained chlorhexidine gluconate (CHG) to clean their entire skin surface 3 times per week for 6 months; group 2 received identical cloths containing only water; and group 3 received no skin treatment. During the study, all newly arrived detainees were invited to enroll. Nares and hand cultures were obtained at baseline and from all current enrollees at 2 and 6 months.

Results: At baseline, S. aureus was isolated from 41.2% and MRSA from 8.0% (nares and/or hand) of 947 enrollees. The average participation rate was 47%. At 6 months, MRSA carriage was 10.0% in group 3 and 8.7% in group 1 tanks (estimated absolute risk reduction [95% confidence interval (CI)], 1.4% [-4.8% to 7.1%]; P = .655). At 6 months, carriage of any S. aureus was 51.1% in group 3, 40.7% in group 1 (absolute risk reduction [95% CI], 10.4% [0.01%-20.1%]; P = .047), and 42.8% (absolute risk reduction [95% CI], 8.3% [-1.4% to 18.0%]; P = .099) in group 2.

Conclusions: Skin cleaning with CHG for 6 months in detainees, compared with no intervention, significantly decreased carriage of S. aureus, and use of water cloths produced a nonsignificant but similar decrease. A nonsignificant decrease in MRSA carriage was found with CHG cloth use.

Trial Registration: ClinicalTrials.gov identifier NCT00785200.
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http://dx.doi.org/10.1086/678606DOI Listing
December 2014

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 22;35(11):1373-82. Epub 2014 Sep 22.

Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California.

Objective: To understand the genotypic spectrum of environmental contamination of Staphylococcus aureus in households and its persistence.

Design: Prospective longitudinal cohort investigation.

Setting: Index participants identified at 2 academic medical centers.

Participants: Adults and children with S. aureus skin infections and their household contacts in Los Angeles and Chicago.

Methods: Household fomites were surveyed for contamination at baseline and 3 months. All isolates underwent genetic typing.

Results: We enrolled 346 households, 88% of which completed the 3-month follow-up visit. S. aureus environmental contamination was 49% at baseline and 51% at 3 months. Among households with a USA300 methicillin-resistant S. aureus (MRSA) body infection isolate, environmental contamination with an indistinguishable MRSA strain was 58% at baseline and 63% at 3 months. Baseline factors associated with environmental contamination by the index subject's infection isolate were body colonization by any household member with the index subject's infection isolate at baseline (odds ratio [OR], 10.93 [95% confidence interval (CI), 5.75-20.79]), higher housing density (OR, 1.47 [95% CI, 1.10-1.96]), and more frequent household fomite cleaning (OR, 1.62 [95% CI, 1.16-2.27]). Household environmental contamination with the index subject's infection strain at 3 months was associated with USA300 MRSA and a synergistic interaction between baseline environmental contamination and body colonization by any household member with the index subject's infection strain.

Conclusions: We found that infecting S. aureus isolates frequently persisted environmentally in households 3 months after skin infection. Presence of pathogenic S. aureus strain type in the environment in a household may represent a persistent reservoir that places household members at risk of future infection.
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http://dx.doi.org/10.1086/678414DOI Listing
November 2014

Hand and nasal carriage of discordant Staphylococcus aureus isolates among urban jail detainees.

J Clin Microbiol 2014 Sep 23;52(9):3422-5. Epub 2014 Jun 23.

Department of Pediatrics, University of Chicago, Chicago, Illinois, USA.

In 928 Dallas County Jail detainees, nasal carriage of Staphylococcus aureus was found in 32.8% (26.5% methicillin-susceptible Staphylococcus aureus [MSSA] and 6.3% methicillin-resistant S. aureus [MRSA]), and hand carriage was found in 24.9% (20.7% MSSA and 4.1% MRSA). Among MRSA nasal carriers, 41% had hand MRSA carriage; 29% with hand MRSA carriage had no nasal S. aureus carriage. The prevalence of carriage was not associated with duration of the jail stay up to 180 days.
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http://dx.doi.org/10.1128/JCM.01190-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4313174PMC
September 2014
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