E M Peterson

University of California, Irvine, Irvine, California, United States

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Publications (172)641.76 Total impact

  • Brett R Hanson · Anatoly Slepenkin · Ellena M Peterson · Ming Tan ·
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    ABSTRACT: Importance: This study investigates a novel mechanism for regulating gene expression in the pathogenic bacterium Chlamydia. The Chlamydia type III secretion (T3S) chaperone Scc4 has been shown to inhibit transcription by RNA polymerase. This study describes physical interactions between Scc4 and the T3S proteins Scc1 and CopN. Furthermore Chlamydia Scc1 and CopN antagonized the inhibitory effects of Scc4 on transcription and growth in a heterologous E. coli system. These results provide evidence that transcription in Chlamydia can be regulated by the T3S system through interactions between T3S proteins.
    Journal of bacteriology 07/2015; 197(20). DOI:10.1128/JB.00379-15 · 2.81 Impact Factor
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    ABSTRACT: Mast cells are known as central players in allergy and anaphylaxis, and they play a pivotal role in host defense against certain pathogens. Chlamydia pneumoniae is an important human pathogen, but it is unclear what role mast cells play during C. pneumoniae infection. We infected C57BL/6 (wild-type [WT]) and mast cell-deficient mice (Kit(W-sh/W-sh) [Wsh]) with C. pneumoniae. Wsh mice showed improved survival compared with WT mice, with fewer cells in Wsh bronchoalveolar lavage fluid (BALF), despite similar levels of cytokines and chemokines. We also found a more rapid clearance of bacteria from the lungs of Wsh mice compared with WT mice. Cromolyn, a mast cell stabilizer, reduced BALF cells and bacterial burden similar to the levels seen in Wsh mice; conversely, Compound 48/80, a mast cell degranulator, increased the number of BALF cells and bacterial burden. Histology showed that WT lungs had diffuse inflammation, whereas Wsh mice had patchy accumulations of neutrophils and perivascular accumulations of lymphocytes. Infected Wsh mice had reduced amounts of matrix metalloprotease-9 in BALF and were resistant to epithelial integral membrane protein degradation, suggesting that barrier integrity remains intact in Wsh mice. Mast cell reconstitution in Wsh mice led to enhanced bacterial growth and normal epithelial integral membrane protein degradation, highlighting the specific role of mast cells in this model. These data suggest that mast cells play a detrimental role during C. pneumoniae infection by facilitating immune cell infiltration into the airspace and providing a more favorable replicative environment for C. pneumoniae. Copyright © 2015 by The American Association of Immunologists, Inc.
    The Journal of Immunology 03/2015; 194(8). DOI:10.4049/jimmunol.1402685 · 4.92 Impact Factor
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    ABSTRACT: Blood stream infection or sepsis is a major health problem worldwide, with extremely high mortality, which is partly due to the inability to rapidly detect and identify bacteria in the early stages of infection. Here we present a new technology termed ‘Integrated Comprehensive Droplet Digital Detection’ (IC 3D) that can selectively detect bacteria directly from milliliters of diluted blood at single-cell sensitivity in a one-step, culture- and amplification-free process within 1.5–4 h. The IC 3D integrates real-time, DNAzyme-based sensors, droplet microencapsulation and a high-throughput 3D particle counter system. Using Escherichia coli as a target, we demonstrate that the IC 3D can provide absolute quantification of both stock and clinical isolates of E. coli in spiked blood within a broad range of extremely low concentration from 1 to 10,000 bacteria per ml with exceptional robustness and limit of detection in the single digit regime.
    Nature Communications 11/2014; 5. DOI:10.1038/ncomms6427 · 11.47 Impact Factor
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    ABSTRACT: The salicylidene acylhydrazide (SA) compounds have exhibited promising microbicidal properties. Previous reports have shown the SA compounds, using cell cultures, to exhibit activity against Chlamydia trachomatis, herpes simplex virus and HIV-1. In addition, using an animal model of a vaginal infection the SA compound INP0341, when dissolved in a liquid, was able to significantly protect mice from a vaginal infection with C. trachomatis. To expand upon this finding, in this report INP0341 was formulated as a vaginal gel, suitable for use in humans. Gelling agents (polymers) with inherent antimicrobial properties were chosen to maximize the total antimicrobial effect of the gel. In vitro formulation work generated a gel with suitable rheology and sustained drug release. A formulation containing 1 mM INP0341, 1.6 wt% Cremophor ELP (solubility enhancer) and 1.5 wt% poly(acrylic acid) (gelling and antimicrobial agent), was chosen for studies of efficacy and toxicity using a mouse model of a vaginal infection. The gel formulation was able to attenuate a vaginal challenge with C. trachomatis, serovar D. Formulations with and without INP0341 afforded protection, but the inclusion of INP0341 increased the protection. Mouse vaginal tissue treated with the formulation showed no indication of gel toxicity. The lack of toxicity was confirmed by in vitro assays using EpiVaginal tissues, which showed that a 24 h exposure to the gel formulation did not decrease the cell viability or the barrier function of the tissue. Therefore, the gel formulation described here appears to be a promising vaginal microbicide to prevent a C. trachomatis infection with the potential to be expanded to other sexually transmitted diseases.
    PLoS ONE 10/2014; 9(10):e110918. DOI:10.1371/journal.pone.0110918 · 3.23 Impact Factor
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    ABSTRACT: Objective: To evaluate whether an ecologic inverse association exists between methicillin-susceptible Staphylococcus aureus (MSSA) prevalence and methicillin-resistant S. aureus (MRSA) prevalence in nursing homes. Methods: We conducted a secondary analysis of a prospective cross-sectional study of S. aureus prevalence in 26 nursing homes across Orange County, California, from 2008-2011. Admission prevalence was assessed using bilateral nares swabs collected from all new residents within 3 days of admission until 100 swabs were obtained. Point prevalence was assessed from a representative sample of 100 residents. Swab samples were plated on 5% sheep blood agar and Spectra MRSA chromogenic agar. If MRSA was detected, no further tests were performed. If MRSA was not detected, blood agar was evaluated for MSSA growth. We evaluated the association between MRSA and MSSA admission and point prevalence using correlation and linear regression testing. Results: We collected 3,806 total swabs. MRSA and MSSA admission prevalence were not correlated (r = -0.40, P = .09). However, MRSA and MSSA point prevalence were negatively correlated regardless of whether MSSA prevalence was measured among all residents sampled (r = -0.67, P = .0002) or among those who did not harbor MRSA (r = -0.41, P = .04). This effect persisted in regression models adjusted for the percentage of residents with diabetes (β = -0.73, P = .04), skin lesions (β = -1.17, P = .002), or invasive devices (β = -1.4, P = .0006). Conclusions: The inverse association between MRSA and MSSA point prevalence and minimal association on admission prevalence suggest MSSA carriage may protect against MRSA acquisition in nursing homes. The minimal association on admission prevalence further suggests competition may occur during nursing home stays.
    Infection Control and Hospital Epidemiology 10/2014; 35(10):1257-1262. DOI:10.1086/678062 · 4.18 Impact Factor
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    ABSTRACT: Chlamydophila pneumoniae (CPn) is a common respiratory pathogen that causes a chronic and persistent airway infection. The elderly display an increased susceptibility and severity to this infection. However, the underlying mechanisms are not well understood. Dendritic cells (DCs) are the initiators and regulators of immune responses. Therefore, we investigated the role of DCs in the age-associated increased CPn infection in vitro in humans. Though the expression of activation markers was comparable between the two age groups, DCs from aged subjects secreted enhanced levels of proinflammatory mediators such as TNF-α and CXCL-10 in response to CPn. In contrast, the secretion of IL-10 and innate interferons, IFN-α and IFN-λ, was severely impaired in DCs from aged donors. The increased activation of DCs from aged subjects to CPn also resulted in enhanced proliferation of CD4 and CD8 T cells in a DC-T coculture. Furthermore, T cells primed with CPn-stimulated DCs from aged subjects secreted increased levels of IFN-γ and reduced levels of IL-10 compared to DCs obtained from young subjects. In summary, DCs from the elderly displayed enhanced inflammatory response to CPn which may result in airway remodeling and increase the susceptibility of the elderly to respiratory diseases such as asthma.
    Mediators of Inflammation 09/2014; 2014:436438. DOI:10.1155/2014/436438 · 3.24 Impact Factor
  • Jay M Bhatt · Ellena M Peterson · Sunil P Verma ·
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    ABSTRACT: The effectiveness of a Cidex-based decontamination protocol was analyzed for its effectiveness in cleaning various components of a flexible fiberoptic laryngoscope (FFL), including the handle, eyepiece, and detachable light cable. A random microbiological sampling and aerobic bacterial culture analysis of 6 FFL eyepieces, 6 FFL driver handles, and 5 light cables prior to patient use was performed. Of 17 samples collected, 7 (41%) were contaminated with bacterial organisms. Organisms recovered represented both environmental organisms from skin and oral flora origin. This study demonstrates that potential contaminants may be present on FFL eyepieces and light cables, which are commonly overlooked in the cleaning protocols of a standard otolaryngology clinic.
    Otolaryngology Head and Neck Surgery 12/2013; 150(2). DOI:10.1177/0194599813513424 · 2.02 Impact Factor
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    ABSTRACT: Chlamydia pneumoniae (CP) lung infection can induce chronic lung inflammation and is associated with not only acute asthma but also COPD exacerbations. However, in mouse models of CP infection, most studies have investigated specifically the acute phase of the infection and not the longer-term chronic changes in the lungs. We infected C57BL/6 mice with 5×10(5) CP intratracheally and monitored inflammation, cellular infiltrates and cytokine levels over time to investigate the chronic inflammatory lung changes. While bacteria numbers declined by day 28, macrophage numbers remained high through day 35. Immune cell clusters were detected as early as day 14 and persisted through day 35, and stained positive for B, T, and follicular dendritic cells, indicating these clusters were inducible bronchus associated lymphoid tissues (iBALTs). Classically activated inflammatory M1 macrophages were the predominant subtype early on while alternatively activated M2 macrophages increased later during infection. Adoptive transfer of M1 but not M2 macrophages intratracheally 1 week after infection resulted in greater lung inflammation, severe fibrosis, and increased numbers of iBALTS 35 days after infection. In summary, we show that CP lung infection in mice induces chronic inflammatory changes including iBALT formations as well as fibrosis. These observations suggest that the M1 macrophages, which are part of the normal response to clear acute C. pneumoniae lung infection, result in an enhanced acute response when present in excess numbers, with greater inflammation, tissue injury, and severe fibrosis.
    PLoS ONE 10/2013; 8(10):e77447. DOI:10.1371/journal.pone.0077447 · 3.23 Impact Factor
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    ABSTRACT: Background: MRSA carriers experience a high risk of MRSA infection in the 6 months after hospital discharge. Reducing carriage during this critical period through decolonization may prevent a meaningful amount of infections and morbidity in MRSA carriers. Methods: MRSA carriage was assessed in an ongoing randomized clinical trial of recently hospitalized MRSA carriers comparing post-discharge education (EDU) to education plus decolonization (DCL). DCL was comprised of serial 5-day courses of twice daily mupirocin, once daily 4% CHG skin cleansing of the body with rinsing, and twice daily 0.12% CHG oral rinse. These 5-day courses were repeated twice monthly for 6 months. Enrollment cultures were taken of the bilateral nares, throat, axilla/groin (as a single swab), and wound (if present), at baseline and months 1, 3, and 6 following enrollment. Carriage proportions were compared between arms by visit and site using chi-square tests. Results: Among the 1,669 randomized patients included in this analysis (n=835 in EDU arm and n=834 in DCL arm), visit completion was 72% at 1 month (M1), 62% at 3 months (M3), and 50% at 6 months (M6) (trial ongoing). At enrollment, there were no differences in MRSA carriage between the arms for each site and any site. Significantly greater reductions were seen in the DCL arm for all sites and all intervention visits (P<0.05) with the exception of wounds at M1 and M6 visits, which were affected by small sample size. At M6, the DCL arm had a 48% (95% CI: 36, 57) greater reduction in MRSA carriage at any body site. For specific body sites at M6, the following percent reductions were seen: nares 56% (CI: 43, 65), throat 34% (CI: 6, 54), axilla/groin 54% (CI: 34, 68), and wound 41% (-15, 70). Conclusion: Post-discharge decolonization plus MRSA education of recently hospitalized MRSA carriers is more effective than MRSA education alone in reducing colonization at multiple body sites. The impact of this intervention on MRSA infections in the high risk post-discharge period remains to be seen. Despite the reduction, carriers persist in both arms. It is not yet known if those who do not adhere to or fail decolonization have higher risks of disease.
    IDWeek 2013 Meeting of the Infectious Diseases Society of America; 10/2013
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    ABSTRACT: To investigate the performance of screening rectal cultures obtained 2 weeks before transrectal prostate biopsy to detect fluoroquinolone-resistant organisms and again at transrectal prostate biopsy. After institutional review board approval for observational study, we obtained a rectal culture on patients identified for a prostate biopsy but before antibiotic prophylaxis from September 12, 2011 to April 23, 2012. The specimen was cultured onto MacConkey agar with and without 1 μg/mL ciprofloxacin. We then obtained a second rectal culture immediately before prostate biopsy after 24 hours of ciprofloxacin prophylaxis. All cultures were blinded to the practitioner until the end of the study. Of 108 patients enrolled, 58 patients had both rectal cultures for comparison. The median time duration between cultures was 14 (6-119) days. There were 54 of 58 concordant pairs (93%), which included 47 negative cultures and 7 positive cultures; 2 patients (3%) who were culture negative from the first screening culture became positive at biopsy. Sensitivity, specificity, negative, positive predictive values, and area under the operator curve were 95.9%, 77.8%, 95.9%, 77.8%, and 0.868, respectively. When Pseudomonas spp. are removed from the analysis, the area under the curve is increased to 0.927. Screening rectal cultures 2 weeks before prostate biopsy has favorable test performance, suggesting screening cultures give an accurate estimate of fluoroquinolone-resistant colonization.
    Urology 07/2013; 82(1):67-73. DOI:10.1016/j.urology.2013.02.068 · 2.19 Impact Factor
  • Michael A. Liss · Kristen K. Nakamura · Ellena M. Peterson ·

    The Journal of Urology 04/2013; 189(4):e475. DOI:10.1016/j.juro.2013.02.800 · 4.47 Impact Factor
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    ABSTRACT: We assessed characteristics associated with community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) carriage among residents of 22 nursing homes. Of MRSA-positive swabs, 25% (208/824) were positive for CA-MRSA. Median facility CA-MRSA percentage was 22% (range, 0%-44%). In multivariate models, carriage was associated with age less than 65 years (odds ratio, 1.2; [Formula: see text]) and Hispanic ethnicity (odds ratio, 1.2; [Formula: see text]). Interventions are needed to target CA-MRSA.
    Infection Control and Hospital Epidemiology 03/2013; 34(3):325-6. DOI:10.1086/669519 · 4.18 Impact Factor
  • Michael A Liss · Ellena M Peterson · Brian Johnston · Kathryn Osann · James R Johnson ·
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    ABSTRACT: Objective: To identify the prevalence and characteristics of fluoroquinolone-resistant (FQ-R) Escherichia coli ST131 isolates in men undergoing ultrasound-guided transrectal prostate biopsy (TPB). Materials and methods: Twenty-seven FQ-R E coli isolates from rectal swabs from 136 men undergoing TPB at 3 institutions in southern California (January 2009 to March 2010), with a focus on repeat biopsy patients, were assessed for E coli phylogenetic group, sequence type ST131 status, extended virulence genotype, pulsed-field gel electrophoresis profile, and antimicrobial susceptibility profile. Results: ST131 accounted for 70% of the 27 FQ-R pre-TPB E coli rectal isolates, including 82% of those from non-Asians vs 20% from Asians (P = .017). ST131 was associated negatively with prebiopsy enemas and positively with previous TPB. Compared with non-ST131 isolates, the ST131 isolates had a significantly higher prevalence of 4 virulence genes (sat, usp, ompT, and malX), distinctive virulence profiles, and numerically higher virulence scores (median, 12 vs 8), but similar antimicrobial resistance scores. Most rectal ST131 isolates exhibited pulsed-field gel electrophoresis profiles typical of clinical ST131 isolates. Conclusion: In our locale, the epidemic multidrug-resistant ST131 clonal group accounts for 70% of FQ-R rectal E coli isolates among men undergoing TPB. Such ST131 isolates have distinctive virulence profiles, are extensively antimicrobial-resistant, and are negatively associated with Asian race. Further investigation is needed regarding risk factors for and clinical consequences of colonization with such strains among men undergoing TPB.
    Urology 01/2013; 81(3). DOI:10.1016/j.urology.2012.10.056 · 2.19 Impact Factor
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    Michael A Liss · Kristen K Nakamura · Ellena M Peterson ·
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    ABSTRACT: A transrectal prostate biopsy is the most common procedure used to establish the diagnosis of prostate cancer. Prior to biopsy, patients are commonly given ciprofloxacin for prophylaxis. However, a complication of the procedure is infection with ciprofloxacin-resistant organisms, in particular resistant Escherichia coli. In order to identify patients carrying ciprofloxacin-resistant E. coli, so as to tailor their antibiotic prophylaxis, rectal swabs are screened using selective broth and/or solid medium. In our evaluation, we compared broth enrichment and direct plating techniques by using brain heart infusion broth and MacConkey agar containing 1 μg/ml or 10 μg/ml of ciprofloxacin. Of the 100 patients included in the study, 20 were colonized with ciprofloxacin-resistant organisms, 19 of which were E. coli. There was no significant difference (P > 0.1) between the culture methods or the ciprofloxacin concentrations in the medium when identifying patients with ciprofloxacin-resistant E. coli; however, broth enrichment using 1 μg/ml ciprofloxacin was the most sensitive at 100%, but it was the least specific. Direct plating of rectal swabs onto MacConkey agar containing 10 μg/ml of ciprofloxacin was 100% specific and missed only 1 positive specimen, with a sensitivity of 94.7%; this method was the most cost-effective. Therefore, direct plating of rectal swabs onto selective medium proved to be a sensitive and cost-effective approach in identifying patients colonized with ciprofloxacin-resistant E. coli.
    Journal of clinical microbiology 11/2012; 51(1). DOI:10.1128/JCM.02158-12 · 3.99 Impact Factor
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    ABSTRACT: Chlorhexidine and mupirocin are used in healthcare facilities to eradicate methicillin-resistant Staphylococcus aureus (MRSA) carriage. The objective of this study was to assess the frequency of chlorhexidine and mupirocin resistance in isolates from nares carriers in multiple nursing homes and to examine characteristics associated with resistance. Nasal swab samples were collected from approximately 100 new admissions and 100 current residents in 26 nursing homes in Orange County, CA from October 2008-May 2011. MRSA isolates were tested for susceptibility using broth microdilution, disk diffusion, and E-test; for genetic relatedness using pulsed-field gel electrophoresis; and for qac gene carriage by PCR. Characteristics of the nursing homes and their residents were collected from the Medicare Minimum Data Set and Long Term Care Focus. A total of 829 MRSA isolates were obtained from swabbing 3806 residents in 26 nursing homes. All isolates had a chlorhexidine MIC <= 4 mcg/ml. Five (0.6%) isolates harbored the qacA/B gene loci. Mupirocin resistance was identified in 101 (12%) isolates with 78 (9%) isolates exhibiting high-level mupirocin resistance (HLMR). HLMR rates per facility ranged from 0-31%. None of the isolates with HLMR displayed qacA/B while two isolates carried qacA and exhibited low-level mupirocin resistance. HLMR was associated with having a multi-drug resistant MRSA isolate (OR=2.69, p=0.004), a history of MRSA (OR=2.34, p<0.001), and dependency in activities of daily living (OR=1.25, p=0.004). In some facilities, HLMR was found in nearly one-third of MRSA isolates. These findings may have implications for the increasingly widespread practice of MRSA decolonization using intranasal mupirocin.
    Antimicrobial Agents and Chemotherapy 11/2012; 57(1). DOI:10.1128/AAC.01623-12 · 4.48 Impact Factor
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    ABSTRACT: Plasmacytoid dendritic cells (pDCs) are known for their robust antiviral response and their pro-tolerance effects towards allergic diseases and tissue engraftments. However, little is known about the role pDCs may play during a bacterial infection, including pulmonary Chlamydia pneumoniae (CP). In this study, we investigated the role of pDCs during pulmonary CP infection. Our results revealed that depletion of pDCs during acute CP infection in mice results in delayed and reduced lung inflammation, with an early delay in cellular recruitment and significant reduction in early cytokine production in the lungs. This was followed by impaired and delayed bacterial clearance from the lungs which then resulted in a severe and prolonged chronic inflammation and iBALT like structures containing large numbers of B and T cells in these animals. We also observed that increasing the pDC numbers in the lung by FLT3L treatment experimentally results in greater lung inflammation during acute CP infection. In contrast to these results, restimulation of T-cells in the draining lymph nodes of pDC-depleted mice induced greater amounts of proinflammatory cytokines than we observed in control mice. These results suggest that pDCs in the lung may provide critical proinflammatory innate immune responses in response to CP infection, but are suppressive towards adaptive immune responses in the lymph node. Thus pDCs in the lung and the draining lymph node appear to have different roles and phenotypes during acute CP infection and may play a role in host immune responses.
    PLoS ONE 10/2012; 7(10):e48655. DOI:10.1371/journal.pone.0048655 · 3.23 Impact Factor
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    ABSTRACT: Background: MRSA prevalence in nursing homes often exceeds that in hospitals, but reasons for this are not well understood. We sought to measure MRSA burden in a large number of nursing homes and identify facility characteristics associated with high MRSA burden. Methods: We performed nasal swabs of residents from 26 nursing homes to measure MRSA importation and point prevalence, and estimate transmission. Using nursing home administrative data, we identified facility characteristics associated with MRSA point prevalence and estimated transmission risk in multivariate models. Results: We obtained 1,649 admission and 2,111 point prevalence swabs. Mean MRSA point prevalence was 24%, significantly higher than mean MRSA admission prevalence, 16%, (paired t-test, p<0.001), with a mean estimated MRSA transmission risk of 16%.In multivariate models, higher MRSA point prevalence was associated with higher admission prevalence (p=0.005) and higher proportions of residents with indwelling devices (p=0.01). Higher estimated MRSA transmission risk was associated with higher proportions of residents with diabetes (p=0.01) and lower levels of social engagement (p=0.03). Conclusions: MRSA importation was a strong predictor of MRSA prevalence, but MRSA burden and transmission were also associated with nursing homes caring for more residents with chronic illnesses or indwelling devices. Frequent social interaction among residents appeared to be protective of MRSA transmission, suggesting that residents healthy enough to engage in group activities do not incur substantial risks of MRSA from social contact. Identifying characteristics of nursing homes at risk for high MRSA burden and transmission may allow facilities to tailor infection control policies and interventions to mitigate MRSA spread.
    BMC Infectious Diseases 10/2012; 12(1):269. DOI:10.1186/1471-2334-12-269 · 2.61 Impact Factor
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    ABSTRACT: Background: The prevalence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is rising in hospitals, but the extent of CA-MRSA penetration into nursing homes has not been well-studied. CA-MRSA, particularly the USA300 strain, may cause increased transmission and more serious clinical disease than traditional healthcare strains. Identifying characteristics associated with higher CA-MRSA prevalence may inform interventions for high risk nursing homes. Methods: Residents of 22 nursing homes in Orange County, California, were previously swabbed for nasal MRSA carriage. MRSA isolates were characterized by spa typing, and isolates with spa type t008 were considered to be CA-MRSA. We tested the association of nursing home characteristics with individual CA-MRSA carriage. Results: Among MRSA isolates, 25% (208/824) were CA-MRSA. The facility median percent of CA-MRSA was 22% (range, 0-44%). In multivariate models, higher odds of CA-MRSA carriage were significantly associated with facilities with more residents under age 65 (OR=1.2, or 20% increased odds per 10% residents under 65, p<0.001) or of Hispanic ethnicity (OR=1.2, or 20% increased odds per 10% Hispanic residents, p=0.002). Our model controlled for whether the isolate was obtained at admission. Conclusion: CA-MRSA prevalence varied widely among nursing homes in a single county. CA-MRSA carriage was higher in facilities with younger residents, mirroring the epidemic of CA-MRSA among younger adults in the community. CA-MRSA prevalence was also higher in nursing homes with more Hispanic residents. Efforts to prevent USA300 and other CA-MRSA strains from becoming endemic in healthcare settings may benefit from targeting high risk nursing homes, particularly if this strain proves to be more transmissible or causes more severe disease in nursing homes.
    IDWeek 2012 Meeting of the Infectious Diseases Society of America; 10/2012
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    ABSTRACT: Salicylidene acylhydrazide compounds have been shown to inhibit bacterial pathogens, including Chlamydia and Neisseria gonorrhoeae. If such compounds could also target HIV-1, their potential use as topical microbicides to prevent sexually transmitted infections would be considerable. In this study, the in vitro anti-HIV-1 activity, cytotoxicity and mechanism of action of several salicylidene acylhydrazides were determined. Inhibitory activity was assessed using TZM-bl cells and primary peripheral blood mononuclear cells (PBMCs) as targets for HIV-1 infection. Antiviral activity was measured against cell-free and cell-associated virus and in vaginal fluid and semen simulants. Since the antibacterial activity of salicylidene acylhydrazides is reversible by Fe(2+), the ability of Fe(2+) and other cations to reverse the anti-HIV-1 activity of the compounds was determined. Real-time PCR was also employed to determine the stage affected in the HIV-1 replication cycle. Four compounds with 50% inhibitory concentrations against HIV-1 of 1-7μM were identified. In vitro toxicity varied but was generally limited. Activity was similar against three R5 clade B primary isolates and whether the target for virus replication was TZM-bl cells or PBMCs. Compounds inhibited cell-free and cell-associated virus and were active in vaginal fluid and semen simulants. Fe(2+), but not other cations, reversed the anti-HIV-1 effect. Finally, the inhibitory effect of the compounds occurred at a post-integration step. In conclusion, salicylidene acylhydrazides were identified with in vitro anti-HIV-1 activity in the micromolar range. The activity of these compounds against other sexually transmitted pathogens makes them potential candidates to formulate for use as a broad-spectrum topical genital microbicide.
    International journal of antimicrobial agents 07/2012; 40(4):354-60. DOI:10.1016/j.ijantimicag.2012.05.023 · 4.30 Impact Factor
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    ABSTRACT: Salicylidene acylhydrazides belong to a class of compounds shown to inhibit bacterial type III secretion (T3S) in pathogenic Gram-negative bacteria. This class of compounds also inhibits growth and replication of Chlamydiae, strict intracellular bacteria that possess a T3S system. In this study a library of 58 salicylidene acylhydrazides was screened to identify inhibitors of Chlamydia growth. Compounds inhibiting growth of both Chlamydia trachomatis and Chlamydophila pneumoniae were tested for cell toxicity and seven compounds were selected for preliminary pharmacokinetic analysis in mice using cassette dosing. Two compounds, ME0177 and ME0192, were further investigated by individual pharmacokinetic analysis. Compound ME0177 had a relatively high peak plasma concentration (C(max)) and area under curve and therefore may be considered for systemic treatment of Chlamydia infections. The other compound, ME0192, had poor pharmacokinetic properties but the highest anti-chlamydial activity in vitro and therefore was tested for topical treatment in a mouse vaginal infection model. ME0192 administered vaginally significantly reduced the infectious burden of C. trachomatis and the number of infected mice.
    The Journal of Antibiotics 06/2012; 65(8):397-404. DOI:10.1038/ja.2012.43 · 1.73 Impact Factor

Publication Stats

4k Citations
641.76 Total Impact Points


  • 1981-2015
    • University of California, Irvine
      • Department of Pathology & Laboratory Medicine
      Irvine, California, United States
  • 2007
    • University of California, Berkeley
      • Department of Molecular and Cell Biology
      Berkeley, California, United States
    • Umeå University
      • Department of Chemistry
      Umeå, Västerbotten, Sweden
  • 2003
    • Lawrence Livermore National Laboratory
      Livermore, California, United States
  • 1992
    • CSU Mentor
      Long Beach, California, United States
  • 1987
    • Orange County Health Care Agency
      Santa Ana, California, United States