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Susan S Huang, Edward Septimus, Ken Kleinman, Julia Moody, Jason Hickok, Lauren Heim, Adrijana Gombosev, Taliser R Avery, Katherine Haffenreffer, Lauren Shimelman, Mary K Hayden, Robert A Weinstein, Caren Spencer-Smith, Rebecca E Kaganov, Michael V Murphy, Tyler Forehand, Julie Lankiewicz, Micaela H Coady, Lena Portillo, Jalpa Sarup-Patel, John A Jernigan, Jonathan B Perlin, Richard Platt, ABATE Infection trial team
Decolonisation with universal chlorhexidine bathing and targeted mupirocin for MRSA carriers did not significantly reduce multidrug-resistant organisms in non-critical-care patients.
Diaz Iglesias, Y., Wilms, T., Vanbever, R., Van Bambeke, F.
Staphylococcus aureus is a highly prevalent pathogen in the respiratory tract of young patients with cystic fibrosis (CF) and causes biofilm-related infections. Here, we set up an in-vitro model of biofilm grown in tryptic soy broth supplemented by glucose and NaCl (TGN) or in artificial sputum medium (ASM) and used it to evaluate on a pharmacodynamic basis the activity of antibiotics used in CF patients and active on staphylococci (meropenem, vancomycin, azithromycin, linezolid, rifampicin, ciprofloxacin, tobramycin). Rheological studies showed that ASM was more elastic than viscous, as also observed for sputa from CF patients, with elastic and viscous moduli respectively similar and slightly lower than those of CF sputa. Biofilms formed by MSSA ATCC 25923 and MRSA ATCC 33591 reached maturity after 24 h, with biomass (measured by crystal violet staining) and metabolic activity (assessed by following resazurin metabolization) being lower in ASM than in TGN, and viability (bacterial counts) being similar in both media. Full concentration-response curves of antibiotics obtained after 24 h incubation of biofilms showed that all antibiotics were drastically less potent and less efficient in ASM than in TGN towards viability, metabolic activity, and biomass. Tobramycin selected for small colony variants, specifically in biofilms grown in ASM; the auxotrophism of these variants could not be established. These data highlight the major influence exerted by the culture medium on S. aureus responsiveness to antibiotics in biofilms. Use of ASM may help to determine effective drug concentrations or to evaluate new therapeutic options against biofilms in CF patients.
Watkins, R. R., Holubar, M., David, M. Z.
Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) result in significant morbidity and mortality for patients in both community and health care settings. This is primarily due to the difficulty in treating MRSA, which is often resistant to multiple classes of antibiotics. Understanding the mechanisms of antimicrobial resistance (AMR) in MRSA provides insight into the optimal use of antimicrobial agents in clinical practice and also underpins critical aspects of antimicrobial stewardship programs. In this review we delineate the mechanisms, prevalence, and clinical importance of resistance to antibiotics licensed in the past 20 years that target MRSA, as well as new drugs in the pipeline which are likely to be licensed soon. Current gaps in scientific knowledge about MRSA resistance mechanisms are discussed, and topics in the epidemiology of AMR in S. aureus that require further investigation are highlighted.
Webb B, Majers J, Healy R, et al.
AbstractBackgroundAntibiotic stewardship is challenging in hematological malignancy patients.MethodsQuasi-experimental implementation study of two antimicrobial stewardship interventions in a hematological malignancy unit: 1) monthly antibiotic cycling for febrile neutropenia: cefepime (+/- metronidazole) and piperacillin-tazobactam and 2) a clinical prediction rule to guide anti-VRE therapy. We used interrupted time-series analysis (ITS) to compare antibiotic use and logistic regression to adjust observed unit-level changes in resistant infections by background community rates.Results2434 admissions spanning 3 years prior and 2 years post-implementation were included. Unadjusted carbapenem and daptomycin use decreased significantly. In ITS analysis, carbapenem use decreased by -230 DOT/1000 patient days (95% confidence interval (CI) -290 to -180), p
Ersoy, S. C., Abdelhady, W., Li, L., Chambers, H. F., Xiong, Y. Q., Bayer, A. S.
Endovascular infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a major healthcare concern, especially infective endocarditis (IE). Standard antimicrobial susceptibility testing (AST) defines most MRSA strains as ‘resistant' to β-lactams, often leading to use of costly and/or toxic treatment regimens. In this investigation, five prototype MRSA strains, representing the range of genotypes in current clinical circulation, were studied. We identified two distinct MRSA phenotypes upon AST using standard media, with or without sodium bicarbonate (NaHCO3) supplementation: one highly susceptible to the anti-staphylococcal β-lactams, oxacillin and cefazolin (‘NaHCO3-responsive’) and one resistant to such agents (‘NaHCO3-nonresponsive’). These phenotypes accurately predicted clearance profiles of MRSA from target tissues in experimental MRSA IE treated with each β-lactam. Mechanistically, NaHCO3 reduced expression of two key genes involved in the MRSA phenotype, mecA and sarA, leading to decreased production of penicillin-binding protein (PBP) 2a (that mediates methicillin resistance), in NaHCO3-responsive (but not in NaHCO3-nonresponsive) strains. Moreover, both cefazolin and oxacillin synergistically killed NaHCO3-responsive strains in the presence of the host defense antimicrobial peptide (LL-37) in NaHCO3-supplemented media. These findings suggest that AST of MRSA strains in NaHCO3-containing media may potentially identify infections caused by NaHCO3-responsive strains that are appropriate for β-lactam therapy.
Methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI) is a major cause of morbidity and mortality in hospitalized patients. Ceftaroline fosamil (CPT) is the only available beta-lactam antibiotic with in vitro and in vivo activities against MRSA. There is currently limited clinical experience with CPT in complicated MRSA BSI.
Materials and Methods
We report a series of eight patients, including three whose strains had reduced susceptibility to vancomycin.
CPT monotherapy was successfully used as salvage therapy for complicated MRSA BSI. The median time to documented clearance was 7 days.
Ceftaroline monotherapy is effective for clearance of refractory MRSA BSI related to implanted devices, endocarditis, and orthopedic infections.
Geriak, M., Haddad, F., Rizvi, K., Rose, W., Kullar, R., LaPlante, K., Yu, M., Vasina, L., Ouellette, K., Zervos, M., Nizet, V., Sakoulas, G.
Vancomycin (VAN) and daptomycin (DAP) are approved as monotherapy for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. A regimen of daptomycin plus ceftaroline (DAP+CPT) has shown promise in published case series of MRSA salvage therapy, but no comparative data exist to compare up front DAP+CPT head-to-head vs. standard monotherapy as initial treatment.In a pilot study, we evaluated 40 adult patients who were randomized to receive DAP 6-8 mg/kg/d + CPT 600 mg IV q8 h (n=17) or standard monotherapy (n=23) with vancomycin (VAN, dosed to achieve serum trough concentrations 15-20 mg/L, n=21) or DAP 6-8 mg/kg/d (n=2). Serum drawn on the first day of bacteremia was sent to a reference laboratory post-hoc for measurement of IL-10 concentrations and correlation to in-hospital mortality.Sources of bacteremia, median Pitt bacteremia scores, Charlson comorbidity indices, and median serum IL-10 serum concentrations were similar in both groups. Although the study was initially designed to examine bacteremia duration, we observed an unanticipated in-hospital mortality difference of 0% (0/17) for combination and 26% (6/23) for monotherapy (P=0.029), causing us to halt the study. Among patients with IL-10 > 5 pg/mL, 0% (0/14) died in the DAP+CPT group vs. 26% (5/19) in the monotherapy group (P=0.057). Here we share the full results of this preliminary (but aborted) assessment of early DAP+CPT versus standard monotherapy in MRSA bacteremia, hoping to encourage a more definitive clinical trial of its potential benefits against this leading cause of infection associated mortality.
Holland T, Davis J.
Jorgensen S, Zasowski E, Trinh T, et al.
AbstractBackgroundMounting evidence suggests the addition of a beta-lactam (BL) to daptomycin (DAP) results in synergistic in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA) and bolsters the innate immune response to infection. The objective of this study was to provide clinical translation to this experimental data and determine if DAP+BL combination therapy results in improved clinical outcomes compared to treatment with DAP alone in patients with MRSA bloodstream infections (BSI).MethodsThis was a retrospective, comparative cohort study conducted at two academic medical centers between 2008 and 2018. Adults with MRSA BSI treated with DAP for ≥72 hours and initiated within five days of culture collection were included. Patients who received a BL for ≥24 hours and initiated within 24 hours of DAP comprised the DAP+BL group. The primary outcome was composite clinical failure (60-day all-cause mortality and/or 60-day recurrence). Analyses were adjusted for confounding using inverse probability of treatment weighting (IPTW).ResultsA total of 229 patients were included (72 DAP+BL and 157 DAP). In unadjusted and IPTW-adjusted analyses, DAP+BL was associated with significantly reduced odds of clinical failure (OR 0.362, 95% CI 0.164, 0.801; aOR 0.386, 95% CI 0.175, 0.853). Adjusted analyses restricted to pre-specified subgroups based on infection complexity and baseline health status, were consistent with the main analysis.ConclusionsThe addition of a BL to DAP was associated with improved clinical outcomes in patients with MRSA BSI. This study provides support to ongoing and future studies evaluating the impact of combination therapy for invasive MRSA infections.
Mergenhagen K, Starr K, Wattengel B, et al.
AbstractBackgroundTreatment of suspected methicillin-resistant Staphylococcus aureus (MRSA) is a cornerstone of many antibiotic regimens; however, antibiotics are associated with toxicity. The Department of Veterans Affairs (VA) hospitals screen each patient on admission and transfer for MRSA nares colonization. The objective of this study was to determine the negative predictive value (NPV) of MRSA screening in the determinization of subsequent positive clinical culture for MRSA. High NPVs with MRSA nares screening maybe used as a stewardship tool for de-escalation as well as avoidance of anti-MRSA therapy.MethodsThis was a retrospective cohort study across VA medical centers nationwide from January 1, 2007 to January 1, 2018. Data from patients with MRSA nares screening upon admission or transfer were obtained from the VA Corporate Data Warehouse. Subsequent clinical cultures within 7 days of the nares swab were evaluated for presence of MRSA. Sensitivity, specificity, positive predictive values (PPVs), and NPVs were calculated for the entire cohort, as well as subgroups for specific culture sites.ResultsThis cohort yielded 561,325 clinical cultures from a variety of anatomical sites. The sensitivity and specificity for positive MRSA clinical culture were 67.4% and 81.2%, respectively. The NPV of MRSA nares screening for ruling out MRSA infection was 96.5%. The NPV for bloodstream infections was 96.5%, for intra-abdominal cultures was 98.6%, for respiratory cultures was 96.1%, for wound cultures was 93.1%, and for cultures from the urinary system was 99.2%.ConclusionGiven the high NPVs, MRSA nares screening may be a powerful stewardship tool for de-escalation and avoidance of empirical anti-MRSA therapy.
Staphylococcus aureus and beta-hemolytic streptococci (BHS) diseases disproportionately affect populations in middle/low-income countries. To assess if this disparity is reflected in colonization by these organisms, we compared their colonization frequency among children from different socioeconomic status (SES) communities in a city with high income inequality.
Between May–August 2014, we collected nasal and throat swabs to investigate S. aureus and BHS colonization among children who attended private and public pediatric clinics. Patients were classified as high SES, middle/low SES, and slum residents. We investigated the antimicrobial resistance profile, the SCCmec types and the presence of PVL genes among methicillin-resistant S. aureus (MRSA). We also examined the antimicrobial resistance profile and serogroups of BHS.
Of 598 children, 221 (37%) were colonized with S. aureus, of which 49 (22%) were MRSA. MRSA colonization was higher in middle/low SES (n = 18; 14%) compared with high SES (n = 17; 6%) and slum (n = 14; 8%) residents (p = 0.01). All MRSA strains were susceptible to clindamycin, nitrofurantoin, and rifampin. The highest non-susceptibility frequency (42.9%) was observed to erythromycin. SCCmec type V was only found in isolates from high SES children; types I and II were found only in middle/low SES children. Ten (20%) MRSA isolates carried PVL genes. Twenty-four (4%) children were BHS carriers. All BHS (n = 8) found in high SES children and six (67%) isolates from slum patients belonged to group A. All group B streptococci were from middle/low SES children, corresponding to five (71%) of the seven BHS isolated in this group. BHS isolates were susceptible to all drugs tested.
Children from different SES communities had distinct bacterial colonization profiles, including MRSA carriage. Public health officials/researchers should consider SES when assessing disease transmission and control measures.
Yamashita, Y., Nagaoka, K., Kimura, H., Suzuki, M., Konno, S., Fukumoto, T., Akizawa, K., Kaku, N., Morinaga, Y., Yanagihara, K.
The use of macrolides against pneumonia has been reported to improve survival, however, little is known about their efficacy against methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. In this study, we investigated the effect of azithromycin (AZM), and compared it with that of vancomycin (VCM) and daptomycin (DAP), in a murine model of MRSA pneumonia. Mice were infected with MRSA by intratracheal injection, and then treated with AZM, VCM or DAP. The therapeutic effect of AZM, in combination or not with the other drugs, was compared in vivo, whereas the effect of AZM on MRSA growth and toxin mRNA expression was evaluated in vitro. In vivo, the AZM-treated group showed significantly longer survival and fewer bacteria in the lungs 24 h after infection than the untreated group, as well as the other anti-MRSA drug groups. No significant decrease in cytokine levels (IL-6 and MIP-2) in bronchoalveolar lavage fluid or toxin expression levels (hla and spa) was observed following AZM treatment. In vitro, AZM suppressed growth of MRSA in late log phase, but not in stationary phase. No suppressive effect against toxin production was observed following AZM treatment in vitro. In conclusion, contrary to the situation in vitro, AZM was effective against MRSA growth in vivo in our pneumonia model, substantially improving survival. The suppressive effect on MRSA growth at the initial stage of pneumonia could underlie the potential mechanism of AZM action against MRSA pneumonia.
Staphylococcus aureus bacteremia (SAB) is associated with significant morbidity and mortality. We sought to re-define the burden, epidemiology and mortality-associated risk factors of SAB in a large Canadian health region.
Residents (> 18 years) experiencing SAB from 2012 to 2014 were assessed. Incidence rates were calculated using civic census results. Factors associated with 30-day mortality were determined through multivariate logistic regression. Incidence and risk factors for SAB were compared to 2000–2006 data.
780 residents experienced 840 episodes of SAB (MRSA; 20%). Incidence rates increased from 23.5 to 32.0 cases/100,000 from 2012 to 2014; [IRR 1.15 (95% CI 1.07–1.23); p
Eléonore Bulliard, Bruno Grandbastien, Laurence Senn, Gilbert Greub, Dominique S. Blanc
Screening for Methicillin-resistant Staphylococcus aureus (MRSA) is part of many recommendations to control MRSA. Several rapid PCR tests are available commercially and updated versions are constantly released. We aimed to evaluate the performance of three consecutive versions (G3, Gen3 and NxG) of the XpertMRSA test.
Yui Eto, K., Firth, N., Davis, A. M., Kwong, S. M., Krysiak, M., Lee, Y. T., O'Brien, F. G., Grubb, W. B., Coombs, G. W., Bond, C. S., Ramsay, J. P.
Horizontal transfer of plasmids encoding antimicrobial-resistance and virulence determinants has been instrumental in Staphylococcus aureus evolution, including the emergence of community-associated methicillin-resistant S. aureus (CA-MRSA). In the early 1990s the first CA-MRSA isolated in Western Australia (WA), WA-5, encoded cadmium, tetracycline and penicillin-resistance genes on plasmid pWBG753 (~30 kb). WA-5 and pWBG753 appeared only briefly in WA, however, fusidic-acid-resistance plasmids related to pWBG753 were also present in the first European CA-MRSA at the time. Here we characterized a 72-kb conjugative plasmid pWBG731 present in multiresistant WA-5-like clones from the same period. pWBG731 was a cointegrant formed from pWBG753 and a pWBG749-family conjugative plasmid. pWBG731 carried mupirocin, trimethoprim, cadmium and penicillin-resistance genes. The stepwise evolution of pWBG731 likely occurred through the combined actions of IS257, IS257-dependent miniature inverted-repeat transposable elements (MITEs) and the BinL resolution system of the β-lactamase transposon Tn552. An evolutionary intermediate ~42-kb non-conjugative plasmid pWBG715, possessed the same resistance genes as pWBG731 but retained an integrated copy of the small tetracycline-resistance plasmid pT181. IS257 likely facilitated replacement of pT181 with conjugation genes on pWBG731, thus enabling autonomous transfer. Like conjugative plasmid pWBG749, pWBG731 also mobilized non-conjugative plasmids carrying oriT mimics. It seems likely that pWBG731 represents the product of multiple recombination events between the WA-5 pWBG753 plasmid and other mobile genetic elements present in indigenous CA-MSSA. The molecular evolution of pWBG731 saliently illustrates how diverse mobile genetic elements can together facilitate rapid accrual and horizontal dissemination of multiresistance in S. aureus CA-MRSA.
Karau, M. J., Schmidt-Malan, S. M., Yan, Q., Greenwood-Quaintance, K. E., Mandrekar, J., Lehoux, D., Schuch, R., Cassino, C., Patel, R.
Bacteriophage-derived lysins are being developed as anti-infective agents. In an acute osteomyelitis MRSA model, rats receiving no treatment, daptomycin, execabase (CF-301) or daptomycin plus exebacase had means of 5.13, 4.09, 4.65, and 3.57 log10 cfu/gram of bone, respectively. All treated animals had fewer bacteria than untreated animals (P≤0.0001), with daptomycin plus exebacase being more active than daptomycin (P=0.0042) or exebacase (P
Popovich K, Snitkin E, Zawitz C, et al.
AbstractBackgroundJails may facilitate spread of MRSA in urban areas. We examined MRSA colonization at entrance to a large urban jail to determine if there are community transmission networks for MRSA that precede incarceration.MethodsIncarcerated males at the Cook County Jail were enrolled—with enrichment for HIV-positive subjects—within 72hours of intake. Surveillance cultures were collected to determine prevalence of MRSA colonization. Genomic analysis and epidemiologic data were used to identify community transmission networks.ResultsThere were 800 incarcerations (718 individuals) enrolled; 58% were HIV-infected. The prevalence of MRSA colonization at intake was 19%. In multivariate analysis, methamphetamine use, unstable housing, current/recent skin infection, and recent injection drug use were predictors of MRSA. Among HIV patients, recent injection drug use, current skin infection, and HIV care at outpatient Clinic A that emphasizes comprehensive care to the LGBTQ community were predictors of MRSA. 14(45%) of 31 detainees with care at Clinic A had colonization. WGS revealed that the high prevalence of MRSA in Clinic A was not due to clonal spread in the clinic but rather an intermingling of distinct community transmission networks. In contrast, genomic analysis supported spread of USA500 strains within a community network. Members of this USA500 network were more likely to be HIV-infected (p
Individuals with methicillin-resistant Staphylococcus aureus (MRSA) skin and soft tissue infection (SSTI) can be simultaneously colonized with MRSA on multiple body sites. Using whole genome sequencing (WGS), the intrahost relatedness of MRSA colonization and infection isolates was investigated.
In the context of a prospective case–control study of SSTI, we analyzed colonization and infection isolates from US Army Infantry trainees with purulent infection due to MRSA. At the time of clinical presentation for SSTI, culture swabs were obtained from the infection site, as well as from the patient’s nasal, oral, inguinal, and perianal regions. S. aureus culture and susceptibility was performed by standard methods. DNA from MRSA isolates was extracted and libraries were produced. Sequences were generated on an Illumina MiSeq, sequence reads were assembled, and single nucleotide variant (SNV) data were analyzed.
Of 74 trainees with MRSA SSTI, 19 (25.7%) were colonized with MRSA. Ten (52.6%) were colonized on more than one body site. Colonization frequency by anatomic site was as follows: inguinal region (33%), nasal region (30%), perianal region (22%), and oral region (14%). A total of 36 MRSA colonization isolates were characterized. The intrahost median number of SNVs between infection and colonization isolates was 17. Among trainees with recurrent MRSA SSTI, limited intrahost diversity suggests that persistent colonization is a major contributor to recurrence risk.
Among military trainees with MRSA SSTI, genomic characterization of infection and colonization isolates revealed a high degree of strain relatedness. Single acquisition events may account for MRSA colonization and infection in this population.
Dymond A, Davies H, Mealing S, et al.
AbstractBackgroundGenomic surveillance of MRSA identifies unsuspected transmission events and outbreaks. Used proactively, this could direct early and highly targeted infection control interventions to prevent ongoing spread. Here, we evaluate the cost effectiveness of this intervention in a model that compared whole genome sequencing plus current practice versus current practice alone.MethodsA UK cost-effectiveness study was conducted using an early model built from the perspective of the National Health Service (NHS) and personal social services. Effectiveness of sequencing was based on the relative reduction in total MRSA acquisitions in a cohort of hospitalised patients in the year following their index admissions. Sensitivity analysis was used to illustrate and assess the level of confidence associated with the conclusions of our economic evaluation.ResultsA cohort of 65,000 patients were ran through the model. Assuming that sequencing would result in a 90% reduction in MRSA acquisition, 290 new MRSA cases were avoided. This gave an absolute reduction of 28.8% and avoidance of two MRSA-related deaths. Base case results indicated that the use of routine, proactive MRSA sequencing would be associated with estimated cost savings of over £728,290 per annual hospitalised cohort. The impact in total QALYs was relatively modest, with sequencing leading to an additional 14.28 QALYs gained. Results were most sensitive to changes in the probability of an MRSA negative patient acquiring MRSA during their hospital admission.ConclusionsWe showed that proactive genomic surveillance of MRSA is likely to be cost-effective. Further evaluation is required in the context of a prospective study.
Community- associated methicillin resistant Staphylococcus aureus (CA-MRSA) cause serious infections and rates continue to rise worldwide. Use of geocoded electronic health record (EHR) data to prevent spread of disease is limited in health service research. We demonstrate how geocoded EHR and spatial analyses can be used to identify risks for CA-MRSA in children, which are tied to place-based determinants and would not be uncovered using traditional EHR data analyses.
An epidemiology study was conducted on children from January 1, 2002 through December 31, 2010 who were treated for Staphylococcus aureus infections. A generalized estimated equations (GEE) model was developed and crude and adjusted odds ratios were based on S. aureus risks. We measured the risk of S. aureus as standardized incidence ratios (SIR) calculated within aggregated US 2010 Census tracts called spatially adaptive filters, and then created maps that differentiate the geographic patterns of antibiotic resistant and non-resistant forms of S. aureus.
CA-MRSA rates increased at higher rates compared to non-resistant forms, p = 0.01. Children with no or public health insurance had higher odds of CA-MRSA infection. Black children were almost 1.5 times as likely as white children to have CA-MRSA infections (aOR 95% CI 1.44,1.75, p
Lee, H., Boyle-Vavra, S., Ren, J., Jarusiewicz, J., Sharma, L. K., Hoagland, D. T., Yin, S., Zhu, T., Hevener, K. E., Ojeda, I., Lee, R. E., Daum, R. S., Johnson, M. E.
Methicillin-resistant Staphylococcus aureus (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 vra operon that is conserved among S. aureus strains encodes a three-component signal transduction system (vraTSR) that is responsible for sensing and responding to cell-wall stress. We developed a novel and multi-faceted 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, RT-PCR assays against vraR expression and direct confirmation of interaction with VraS by surface plasmon resonance (SPR) further verified them to be viable hit compounds. 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.
Volk C, Burgdorf S, Edwardson G, et al.
AbstractIntroductionPatient IL-1β and IL-10 responses early in the course of Staphylococcus aureus bacteremia (SaB) are associated with bacteremia duration and mortality. We hypothesized that these responses vary depending on choice of antimicrobial therapy, with particular interest in knowing whether the superior performance of -lactams may be linked to key cytokine signaling pathways.MethodsThree medical centers included 59 patients with SaB (47 MRSA, 12 MSSA) from 2015-2017. In the first 48 h, patients were treated with either a β-lactam (n=24), including oxacillin, cefazolin, or ceftaroline, or a glyco-/lipopeptide (n=35), i.e. vancomycin or daptomycin (VAN/DAP). Patient sera from days 1, 3 and 7 were assayed for IL-1β and IL-10 by ELISA and compared using Mann-Whitney U.ResultsOn day 1 of presentation, IL-10 was elevated in patients with outcomes of mortality (P=0.008) and persistent bacteremia (P=0.034), while no difference occurred in IL-1β. Regarding treatment groups, IL-1β and IL-10 was similar at presentation prior to receiving an antibiotic. Patients treated with β-lactam had higher IL-1β on day 3 (median +5.6 pg/mL; P=0.007) and day 7 (+10.9 pg/ml; P=0.016). Ex vivo, the addition of IL-1 receptor antagonist anakinra to whole blood reduced staphylococcal killing, supporting a functional significance of the host IL-1β response in SaB clearance. β-lactam treated patients had sharper declines in IL-10 than VAN/DAP treated patients at days 3 and 7.
Edit Urbán, Gregory G. Stone
In 2018, the European Committee on Antimicrobial Susceptibility Testing (EUCAST) introduced an intermediate breakpoint for ceftaroline against Staphylococcus aureus. The objective of this study was to compare data on resistance to ceftaroline among methicillin-resistant S. aureus (MRSA) isolates using versions 7.1 (March 2017) and 8.0 (January 2018) of the EUCAST breakpoints.
In China multidrug-resistant bacteria pose a considerable threat to public health. Antimicrobial resistance has weakened the effectiveness of many medicines widely used today. Thus, discovering new antibacterial drugs is paramount in the effort to treat emerging drug-resistant bacteria.
Eravacycline, tigecycline and other clinical routine antibiotics were tested by reference broth micro-dilution method against 336 different strains collected from 11 teaching hospitals in China between 2012 and 2016. These isolates included Enterobacteriaceae, non-fermentative, Staphylococcus spp., Enterococcus, and a number of fastidious organisms. The strains involved in this study possess the most important drug resistance characteristics currently known in China. Drug resistant bacteria such as those producing extended spectrum β-lactamases (ESBL) and carbapenemases (KPC-2 and NDM-1), and those exhibiting colistin resistance (mcr-1) and tigecycline were included in this study. Additionally, methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), β-lactamase positive Haemophilus influenzae, and penicillin resistant Streptococcus pneumoniae (PRSP) were also included.
Eravacycline exhibited good efficacy against all the strains tested, especially for organisms with ESBLs, carbapenemases, and mcr-1 gene compared with tigecycline and other antibiotics tested. The MIC values of eravacycline against carbapenemase producing Enterobacteriaceae and OXA-23-producing A. baumannii were much lower than the MIC values of other antibiotics. MRSA, VRE, β-lactamase positive Haemophilus influenza, and PRSP were sensitive to eravacycline in every strain tested. Furthermore, in most strains tested, the MICs of eravacycline were two to four-fold lower than the MICs of tigecycline.
Eravacycline has shown potent antibacterial activity against common and clinically important antibiotic-resistant pathogens. The MIC distribution of eravacycline was generally lower than that of tigecycline which demonstrates that this new drug is potentially more effective than the existing medications.
Lepak, A. J., Zhao, M., Marchillo, K., VanHecker, J., Andes, D. R.
Omadacycline is a novel aminomethylcycline antibiotic with potent activity against Staphylococcus aureus, including methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA). We investigated the pharmacodynamic activity of omadacycline against 10 MSSA/MRSA strains in the neutropenic murine thigh model. The median 24h AUC/MIC associated with net stasis and 1-log kill was 21.9 and 57.7, respectively.
Rich, H. E., McCourt, C. C., Zheng, W. Q., McHugh, K. J., Robinson, K. M., Wang, J., Alcorn, J. F.
Influenza kills 30-40,000 people each year in the United States, and causes ten times as many hospitalizations. A common complication of influenza is bacterial super-infection, which exacerbates morbidity and mortality from the viral illness. Recently, MRSA has emerged as the dominant pathogen found in bacterial super-infection, with Streptococcus pneumoniae a close second. However, clinicians have few tools to treat bacterial super-infection. Current therapy for influenza/bacterial super-infection consists of treating the underlying influenza infection, adding various antibiotics which are increasingly rendered ineffective by rising bacterial multi-drug resistance. Several groups have recently proposed using the antiviral cytokine interferon lambda (IFN-) as a therapeutic for influenza, as administration of pegylated IFN- improves lung function and survival during influenza by reducing the overabundance of neutrophils in the lung. However, our data suggest that therapeutic IFN- impairs bacterial clearance during influenza super-infection. Specifically, mice treated with an adenoviral vector to overexpress IFN- during influenza infection exhibited increased bacterial burden upon super-infection with either MRSA or S. pneumoniae. Surprisingly, adhesion molecule expression, antimicrobial peptide production, and reactive oxygen species activity were not altered by IFN- treatment. However, neutrophil uptake of MRSA and S. pneumoniae was significantly reduced upon IFN- treatment during influenza super-infection in vivo. Together, these data support the theory that IFN- decreases neutrophil motility and function in the influenza-infected lung, which increases bacterial burden during super-infection. Thus, we believe caution should be exercised in the possible future use of IFN- as therapy for influenza.
Verma, A. K., Bauer, C., Yajjala, V. K., Bansal, S., Sun, K.
Post-influenza methicillin-resistant Staphylococcus aureus (MRSA) infection can quickly develop into severe, necrotizing pneumonia, causing over 50% mortality despite antibiotic treatments. In this study, we investigated the efficacy of antibiotic therapies and the impact of S. aureus α-toxin in a lethal model of influenza and MRSA coinfection. We demonstrate that antibiotics primarily attenuate α-toxin-induced acute lethality, even though both α-toxin-dependent and -independent mechanisms significantly contribute to animal mortality after coinfection. Furthermore, we found that protein synthesis-suppressing antibiotic linezolid has an advantageous therapeutic effect on α-toxin-induced lung damage as measured by protein leak and lactate dehydrogenase (LDH) activity. Importantly, using a Panton–Valentine Leucocidin (PVL)-negative MRSA isolate from patient sputum, we show that linezolid therapy significantly improves animal survival from post-influenza MRSA pneumonia as compared with vancomycin treatment. Rather than improved viral or bacterial control, this advantageous therapeutic effect is associated with significantly attenuated pro-inflammatory cytokine response and acute lung damage in linezolid-treated mice. Together, our findings not only establish a critical role of α-toxin in the extreme mortality of secondary MRSA pneumonia after influenza, but also provide support that linezolid could be a more effective treatment to improve disease outcome.
Denys, G. A., Devoe, N. C., Gudis, P., May, M., Allen, R. C., Stephens, J. T.
E-101 Solution is a first in class myeloperoxidase-mediated antimicrobial developed for topical application. It is composed of porcine myeloperoxidase (pMPO), glucose oxidase (GO), glucose, sodium chloride, and specific amino acids in an aqueous solution. Once activated, the reactive species hydrogen peroxide (H2O2), hypochlorous acid and singlet oxygen are generated. We evaluated the treatment effect of E-101 solution and its oxidative products on ultrastucture changes and microbicidal activity against methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli. Time kill and transmission electron microscopy studies were also performed using formulations with pMPO or GO omitted. The glutathione membrane protection assay was used to study the neutralization of reactive oxygen species. The potency of E-101 solution was also measured in the presence of serum and whole blood by MIC and MBC determinations. E-101 solution demonstrated rapid bactericidal activity and ultracellular changes in MRSA and E. coli cells. When pMPO was omitted, high levels of H2O2 generated from GO and glucose demonstrated slow microbicidal activity with minimal cellular damage. When GO was omitted from the formulation no antimicrobial activity or cellular damage was observed. Protection from exposure to E-101 solution reactive oxygen species in the glutathione protection assay was competitive and temporary. E-101 solution maintained its antimicrobial activity in the presence of inhibitory substances such as serum and whole blood. E-101 solution is a potent myeloperoxidase enzyme system with multiple oxidative mechanisms of action. Our findings suggest the primary site that E-101solution exerts microbicidal action is the cell membrane by inactivation of essential cell membrane components.
Daniela Dolce, Stella Neri, Laura Grisotto, Silvia Campana, Novella Ravenni, Francesca Miselli, Erica Camera, Lucia Zavataro, Cesare Braggion, Ersilia V. Fiscarelli, Vincenzina Lucidi, Lisa Cariani, Daniela Girelli, Nadia Faelli, Carla Colombo, Cristina Lucanto, Mariangela Lombardo, Giuseppe Magazzù, Antonella Tosco, Valeria Raia, Serena Manara, Edoardo Pasolli, Federica Armanini, Nicola Segata, Annibale Biggeri, Giovanni Taccetti
by Daniela Dolce, Stella Neri, Laura Grisotto, Silvia Campana, Novella Ravenni, Francesca Miselli, Erica Camera, Lucia Zavataro, Cesare Braggion, Ersilia V. Fiscarelli, Vincenzina Lucidi, Lisa Cariani, Daniela Girelli, Nadia Faelli, Carla Colombo, Cristina Lucanto, Mariangela Lombardo, Giuseppe Magazzù, Antonella Tosco, Valeria Raia, Serena Manara, Edoardo Pasolli, Federica Armanini, Nicola Segata, Annibale Biggeri, Giovanni Taccetti
Background Few studies, based on a limited number of patients using non-uniform therapeutic protocols, have analyzed Methicillin-resistant Staphylococcus aureus (MRSA) eradication. Methods In a randomized multicenter trial conducted on patients with new-onset MRSA infection we evaluated the efficacy of an early eradication treatment (arm A) compared with an observational group (B). Arm A received oral rifampicin and trimethoprim/sulfamethoxazole (21 days). Patients’ microbiological status, FEV1, BMI, pulmonary exacerbations and use of antibiotics were assessed. Results Sixty-one patients were randomized. Twenty-nine (47.5%) patients were assigned to active arm A and 32 (52.5%) patients to observational arm B. Twenty-nine (47.5%) patients, 10 patients in arm A and 19 in arm B, dropped out of the study. At 6 months MRSA was eradicated in 12 (63.2%) out of 19 patients in arm A while spontaneous clearance was observed in 5 (38.5%) out of 13 patients in arm B. A per-protocol analysis showed a 24.7% difference in the proportion of MRSA clearance between the two groups (z = 1.37, P(Z>z) = 0.08). Twenty-seven patients, 15 (78.9%) out of 19 in arm A and 12 (92.3%) out of 13 in arm B, were able to perform spirometry. The mean (±SD) FEV1 change from baseline was 7.13% (±14.92) in arm A and -1.16% (±5.25) in arm B (p = 0.08). In the same period the BMI change (mean ±SD) from baseline was 0.54 (±1.33) kg/m2 in arm A and -0.38 (±1.56) kg/m2 in arm B (p = 0.08). At 6 months no statistically significant differences regarding the number of pulmonary exacerbations, days spent in hospital and use of antibiotics were observed between the two arms. Conclusions Although the statistical power of the study is limited, we found a 24.7% higher clearance of MRSA in the active arm than in the observational arm at 6 months. Patients in the active arm A also had favorable FEV1 and BMI tendencies.
Methicillin-resistant Staphylococcus aureus (MRSA) is associated with significant morbidity and mortality and has resultant important economic and societal costs underscoring the need for accurate surveillance. In recent years, prevalence rates reported in East Africa have been inconsistent, sparking controversy and raising concern.
We described antimicrobial susceptibility patterns of Staphylococcus aureus isolates cultured from patients within the Internal Medicine department of the largest public healthcare facility in East and Central Africa- the Kenyatta National Hospital (KNH) in Nairobi, Kenya. Routine antimicrobial susceptibility data from non-duplicate Staphylococcus aureus isolates cultured between the years 2014–2016 from the medical wards in KNH were reviewed.
Antimicrobial susceptibility data from a total of 187 Staphylococcus aureus isolates revealed an overall MRSA prevalence of 53.4%. Isolates remained highly susceptible to linezolid, tigecycline, teicoplanin and vancomycin.
The prevalence of MRSA was found to be much higher than that reported in private tertiary facilities in the same region. Careful interrogation of antimicrobial susceptibility results is important to uproot any red herrings and reserve genuine cause for alarm, as this has a critical bearing on health and economic outcomes for a population.
Galar, A., Weil, A. A., Dudzinski, D. M., Munoz, P., Siedner, M. J.
Staphylococcus aureus prosthetic valve endocarditis (PVE) remains among the most morbid bacterial infections, with mortality estimates ranging from 40% to 80%. The proportion of PVE cases due to methicillin-resistant Staphylococcus aureus (MRSA) has grown in recent decades, to account for more than 15% of cases of S. aureus PVE and 6% of all cases of PVE. Because no large studies or clinical trials for PVE have been published, most guidelines on the diagnosis and management of MRSA PVE rely upon expert opinion and data from animal models or related conditions (e.g., coagulase-negative Staphylococcus infection). We performed a review of the literature on MRSA PVE to summarize data on pathogenic mechanisms and updates in epidemiology and therapeutic management and to inform diagnostic strategies and priority areas where additional clinical and laboratory data will be particularly useful to guide therapy. Major updates discussed in this review include novel diagnostics, indications for surgical management, the utility of aminoglycosides in medical therapy, and a review of newer antistaphylococcal agents used for the management of MRSA PVE.
Inagaki K, Lucar J, Blackshear C, et al.
AbstractBackgroundInformation on outcomes of methicillin-susceptible and -resistant S. aureus (MSSA and MRSA, respectively) bacteremia, particularly readmission is scarce, and require further research to inform optimal patient care.MethodsWe performed a retrospective analysis using the 2014 Nationwide Readmissions Database, capturing 49.3% of US hospitalizations. We identified MSSA and MRSA bacteremia using International Classification of Diseases, Ninth Revision, Clinical Modification among patients aged ≥18 years. Thirty-day readmission, mortality, length of stay and costs were assessed using Cox proportional hazards regression, logistic regression, Poisson regression, and generalized linear model with gamma distribution and log link, respectively.ResultsOf 92089 (standard error, SE: 1905) patients with S. aureus bacteremia, 48.5% (SE: 0.4%) had MRSA bacteremia. Thirty-day readmission rate was 22% (SE: 0.3) overall with no difference between MRSA and MSSA, but MRSA bacteremia had more readmission for bacteremia recurrence (hazard ratio: 1.17 [95% confidence interval, CI: 1.02-1.35]), higher in-hospital mortality (odds ratio: 1.15 [95%CI: 1.07-1.22]), and longer hospitalization (incidence rate ratio: 1.08 [95%CI: 1.06-1.11]). Readmission with bacteremia recurrence was particularly more common among patients with endocarditis, immunocompromising comorbidities, and drug abuse. The cost of readmission was $12425 (SE: 174) /case overall, and $19186 (SE: 623) in those with bacteremia recurrence.ConclusionsThirty-day readmission after S. aureus bacteremia is common and costly. MRSA bacteremia is associated with readmission for bacteremia recurrence, increased mortality, and longer hospitalization. Efforts should continue to optimize patient care, particularly for those with risk factors, to decrease readmission and associated morbidity and mortality in patients with S. aureus bacteremia.
Li L, Wang G, Cheung A, et al.
AbstractBackgroundMgrA is an important global virulence gene regulator in Staphylococcus aureus. In the present study, the role of mgrA in host-pathogen interactions related to virulence was explored in both methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) strains.MethodsIn vitro susceptibilities to human defense peptides (HDPs), adherence to fibronectin (Fn) and endothelial cells (ECs), ECs damage, -toxin production, the expression of global regulator (e.g., agr RNAIII) and its downstream effectors (e.g., -toxin [hla] and Fn binding protein A [fnbA]), MgrA binding to fnbA promoter and effect on HDP-induced mprF and dltA expression were analyzed. The impact of mgrA on virulence was carried out using a mouse bacteremia model.ResultsmgrA mutants displayed significantly higher susceptibilities to the HDPs which might be related to the less HDP-induced mprF and dltA expression, but decreased Fn and ECs adherence, ECs damage, -toxin production, agr RNAIII, hla and fnbA expression, and attenuated virulence in the bacteremia model as compared to their respective parental and mgrA-complemented strains. Importantly, a direct binding of MgrA protein to fnbA promoter was observed.ConclusionsThese results suggest that mgrA mediates host-pathogen interactions and virulence, and may provide a novel therapeutic target for invasive S. aureus infections.
There have been no reports regarding clinical features and molecular characteristics of childhood methicillin-susceptible Staphylococcus aureus (MSSA) infections in Taiwan.
We prospectively collected clinical S. aureus isolates from patients aged
Mody L, Washer L, Kaye K, et al.
AbstractBackgroundThe impact of healthcare personnel hand contamination in multidrug-resistant organism (MDRO) transmission is important and well studied; however, the role of patient hand contamination needs to be characterized further.MethodsPatients from 2 hospitals in southeast Michigan were recruited within 24 hours of arrival to their room and followed prospectively using microbial surveillance of nares, dominant hand, and 6 high-touch environmental surfaces. Sampling was performed on admission, days 3 and 7, and weekly until discharge. Paired samples of methicillin-resistant Staphylococcus aureus (MRSA) isolated from the patients’ hand and room surfaces were evaluated for relatedness using pulsed-field gel electrophoresis and staphylococcal cassette chromosome mec, and Panton-Valentine leukocidin typing.ResultsA total of 399 patients (mean age, 60.8 years; 49% male) were enrolled and followed for 710 visits. Fourteen percent (n = 56/399) of patients were colonized with an MDRO at baseline; 10% (40/399) had an MDRO on their hands. Twenty-nine percent of rooms harbored an MDRO. Six percent (14/225 patients with at least 2 visits) newly acquired an MDRO on their hands during their stay. New MDRO acquisition in patients occurred at a rate of 24.6/1000 patient-days, and in rooms at a rate of 58.6/1000 patient-days. Typing demonstrated a high correlation between MRSA on patient hands and room surfaces.ConclusionsOur data suggest that patient hand contamination with MDROs is common and correlates with contamination on high-touch room surfaces. Patient hand hygiene protocols should be considered to reduce transmission of pathogens and healthcare-associated infections.
Watkins R, Deresinski S.
AbstractOmadacycline, an aminomethylcycline, is a novel member of the tetracycline class of antibiotics. It has received approval by the U.S. Food and Drug Administration (FDA) for treatment of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSIs) and is available in both oral and intravenous formulations. It is also being evaluated in clinical trials for the treatment of cystitis and pyelonephritis. The omadacycline molecule was designed to overcome tetracycline resistance and has broad spectrum activity that includes gram-positive bacteria, gram-negative bacteria, anaerobes, atypicals, and other drug-resistant strains like methicillin-resistant Staphylococcus aureus (MRSA), as well as Yersinia pestis and Bacillus anthracis, organisms of biodefense interest. Omadacycline has minimal drug-drug pharmacokinetic interactions and a favorable safety profile, with the most common adverse events being gastrointestinal symptoms.
Mroue, N., Arya, A., Brown Gandt, A., Russell, C., Han, A., Gavrish, E., LaFleur, M.
It is often difficult to cure endocarditis, osteomyelitis, and device-associated infections caused by Gram-positive pathogens, despite therapy with clinically appropriate antibiotics. This may be due to antibiotic tolerance or resistance development. Acyldepsipeptides are a class of bactericidal compounds active against a variety of clinically important Gram-positive bacteria, including staphylococci, streptococci, and enterococci. ADEPs activate the ClpP protease, killing high-density, non-dividing cultures of bacteria, tolerant to approved classes of antibiotics. Acyldepsipeptide analog 4 (ADEP4) was active against a panel of drug resistant Gram-positive pathogens in MIC assays with no pre-existing resistance detected. Killing of stationary phase cultures was observed when ADEP4 was combined with multiple classes of approved antibiotics. Additionally, a hollow-fiber infection model was used to assess the effects of ADEP4 antibiotic combinations on bacterial killing and resistance development. These studies were performed on high-density cultures of methicillin-resistant S. aureus (MRSA), methicillin-susceptible S. aureus (MSSA), and vancomycin-resistant Enterococcus faecalis (VRE). None of the approved antibiotics linezolid, ampicillin, or oxacillin had bactericidal activity when tested alone under these conditions. ADEP4 initially caused killing, but regrowth of the culture was apparent within 96 hours due to resistance. Combinations of ADEP4 with linezolid or oxacillin caused substantially improved killing of MRSA and MSSA cultures respectively, and no regrowth due to resistance was observed. The combination of ADEP4 and ampicillin eradicated cultures of VRE to the limit of detection within 52 hours. These data suggest that combining ClpP activators with traditional antibiotics may be a good strategy to treat complicated Gram-positive infections.
Veronica Weterings, Jacobien Veenemans, Miranda van Rijen, Jan Kluytmans
We determined the prevalence of MRSA nasal carriage upon hospital admission, among patients who were screened preoperatively for nasal S. aureus carriage between 2010 and 2017. Secondly, we aimed to evaluate the prevalence of MRSA carriers without the standard risk factors.
Jackson K, Gokhale R, Nadle J, et al.
AbstractBackgroundPublic health and infection control prevention and surveillance efforts in the United States have primarily focused on methicillin-resistant Staphylococcus aureus (MRSA) prevention over past decades. We describe the public health importance of MSSA in selected communities.MethodsWe analyzed active, population-based surveillance data from CDC’s Emerging Infections Program for invasive S. aureus (SA) infections in eight counties from five U.S. states. A case was isolation of SA from a normally sterile site in a surveillance area resident during 2016. Cases were considered healthcare-associated if culture obtained >3 days after admission or if associated with dialysis, hospitalization, surgery, or long-term care facility (LTCF) residence within 1 year prior, or central vascular catheter ≤2 days prior. Incidence per 100,000 census population was calculated and a multivariate logistic regression model with random intercepts for state compared MSSA risk factors with MRSA.ResultsInvasive MSSA incidence (31.3/100,000) was 1.8 times higher than MRSA (17.5/100,000). Persons with MSSA were more likely than those with MRSA to have no underlying medical conditions (adjusted odds ratio [aOR] 2.06, 95% confidence interval [CI], 1.26–3.39) and less likely to have prior hospitalization (aOR 0.70, 95% CI, 0.60–0.82) or LTCF residence (aOR 0.37, 95% CI, 0.29-0.47). MSSA accounted for 59.7% of healthcare-associated cases, and 60.1% of deaths.ConclusionsAlthough MRSA tended to be more associated with healthcare exposures, invasive MSSA is a substantial public health problem in these areas. Public health and infection control prevention efforts should consider MSSA prevention in addition to MRSA.
Austin E, Sullivan S, Macesic N, et al.
AbstractBackgroundUnderstanding the changing epidemiology of Staphylococcus aureus bacteremia, as well as the clinical variables associated with poor outcomes, can yield insight into potential interventions.MethodsThis study was a retrospective, observational cohort study of adult patients at an academic medical center in New York City who had S. aureus bloodstream infection between January 1, 2007 and December 31, 2015. Participants were divided into three periods: Group 1 (2007-09), Group 2 (2010-12), and Group 3 (2013-15) for analysis of trends. All clinical strains were genotyped (spa.) The main outcome was 30-day all-cause mortality.ResultsThere were 1264 episodes of MSSA and 875 episodes of MRSA bacteremia, with a rising proportion due to MSSA (55% G1;. 59% G2; 63% G3, p = 0.03.) There were no significant changes in variables such as average age, gender, Charlson score, proportion of hospital-onset (HO) infections, and distribution of dominant strain genotypes. Mortality in MRSA infection was unchanged (25% G1; 25% G2; 26% G3), while mortality in MSSA infection significantly declined (18% G1; 18% G2; 13% G3.) From 2007-2015, there was a decrease in the average time to anti-staphylococcal therapy (AST) in MSSA infection (3.7 days G1; 3.5 G2; 2.2 G3.) In multivariate analysis, AST within 7 days of initial positive MSSA culture was associated with survival.ConclusionsMortality in MSSA bloodstream infection is declining, associated with a decrease in time to targeted therapy. These results emphasize the potential for rapid diagnostics and early optimization of treatment to impact outcomes in MSSA bacteremia.
Baines, S. L., Jensen, S. O., Firth, N., Goncalves da Silva, A., Seemann, T., Carter, G., Williamson, D. A., Howden, B. P., Stinear, T. P.
Staphylococcus aureus is a significant human pathogen whose evolution and adaptation has been shaped in part by mobile genetic elements (MGEs), facilitating global spread of extensive antimicrobial resistance. However, our understanding of the evolutionary dynamics surrounding MGEs is incomplete, in particular how changes in the structure of multidrug-resistant (MDR) plasmids may influence important staphylococcal phenotypes. Here, we undertook a population- and functional-genomics study of 212 methicillin-resistant S. aureus (MRSA) ST239 isolates collected over 32 years to explore the evolution of the pSK1 family of MDR plasmids; illustrating how these plasmids have co-evolved with and contributed to the successful adaptation of this persistent MRSA lineage. Using complete genomes and temporal phylogenomics we reconstructed the evolution of the pSK1 family lineage from its emergence in the late 1970s, with multiple structural variants arising. Plasmid maintenance and stability was linked to IS256- and IS257-mediated chromosomal integration and disruption of plasmid replication machinery. Overlaying genomic comparisons with phenotypic susceptibility data for gentamicin, trimethoprim and chlorhexidine, it appeared that pSK1 has contributed to enhanced resistance in ST239 MRSA through two mechanisms: (i) acquisition of plasmid-borne resistance mechanisms increasing rates of gentamicin resistance and reduced chlorhexidine susceptibility, and (ii) changes in plasmid configuration linked with further enhancement of chlorhexidine tolerance. While the exact mechanism of enhanced tolerance remains elusive, this research has uncovered a potential evolutionary response of ST239 MRSA to biocides, one which may contribute to the ongoing persistence and adaptation of this lineage within healthcare institutions.
Clarke, R. S., Bruderer, M. S., Ha, K. P., Edwards, A. M.
Co-trimoxazole (SXT) is a combination therapeutic that consists of sulfamethoxazole and trimethoprim that is increasingly used to treat skin and soft-tissue infections caused by methicillin-resistant Staphylococcus aureus (MRSA). However, the use of SXT is limited to the treatment of low-burden, superficial S. aureus infections and its therapeutic value is compromised by the frequent emergence of resistance. As a first step towards the identification of approaches to enhance the efficacy of SXT, we examined the role of bacterial DNA repair in antibiotic susceptibility and mutagenesis. We found that mutants lacking the DNA repair complex RexAB had a modest 2-fold lower SXT MIC than wild-type strains but were killed 50-5000-fold more efficiently by the combination antibiotic at the breakpoint concentration. SXT-mediated DNA damage occurred via both thymidine limitation and the generation of reactive oxygen species, and triggered induction of the SOS response in a RexAB-dependent manner. SOS induction was associated with a 50% increase in the mutation rate, which may contribute to emergence of resistant strains during SXT therapy. In summary, this work determined that SXT caused DNA damage in S. aureus via both thymidine limitation and oxidative stress, which was repaired by the RexAB complex, leading to induction of the mutagenic SOS response. Small molecule inhibitors of RexAB could therefore have therapeutic value by increasing the efficacy of SXT and decreasing the emergence of drug-resistance during treatment of infections caused by S. aureus.
Sandra Valderrama-Beltrán, Sandra Gualtero, Carlos Álvarez-Moreno, Fabian Gil, Álvaro Ruiz-Morales, José Yesid Rodríguez, Johanna Osorio, Ivan Tenorio, Carlos Gómez Quintero, Sebastián Mackenzie, María Alejandra Caro, Alberto Zhong, Gerson Arias, Indira Berrio, Ernesto Martinez, Gloria Cortés, Alejandro De la Hoz, Cesar A. Arias
Methicillin resistant Staphylococcus aureus (MRSA) skin and soft tissue infections (SSTIs) represent a major clinical problem in Colombia. The aim of this study was to evaluate the risk factors associated with MRSA SSTI in Colombia.
G C, B., Sahukhal, G. S., Elasri, M. O.
Staphylococcus aureus is an important human pathogen in both community and health care settings. One of the challenges with S. aureus as a pathogen is its acquisition of antibiotic resistance. Previously, we have shown that deletion of the msaABCR operon reduces cell wall thickness, resulting in decreased resistance to vancomycin in vancomycin-intermediate susceptible S. aureus (VISA). In this study, we investigated the nature of the cell wall defect in the msaABCR operon mutant in the Mu50 (VISA) and USA300 LAC methicillin-resistant Staphylococcus aureus (MRSA) strains. Results showed that msaABCR-mutant cells had decreased crosslinking in both strains. This defect is typically due to increased murein hydrolase activity and/or nonspecific processing of murein hydrolases mediated by increased protease activity in mutant cells. The defect was enhanced by a decrease in teichoic acid content in the msaABCR mutant. Therefore, we propose that deletion of the msaABCR operon results in decreased peptidoglycan crosslinking, leading to increased susceptibility towards cell wall-targeting antibiotics, such as β-lactams and vancomycin. Moreover, we also observed significantly downregulated transcription of early cell wall-synthesizing genes, supporting the finding that msaABCR-mutant cells have decreased peptidoglycan synthesis. More specifically, the msaABCR mutant in the USA300 LAC strain (MRSA) showed significantly reduced expression of the murA gene, whereas the msaABCR mutant in the Mu50 strain (VISA) showed significantly reduced expression of glmU, murA, and murD. Thus, we conclude that the msaABCR operon controls the balance between cell wall synthesis and cell wall hydrolysis, which is required for maintaining a robust cell wall and acquiring resistance to cell wall-targeting antibiotics, such as vancomycin and the β-lactams.
Lopes, A.-A., Yoshii, Y., Yamada, S., Nagakura, M., Kinjo, Y., Mizunoe, Y., Okuda, K.-i.
Staphylococcus aureus is responsible for numerous community outbreaks and is one of the most frequent causes of nosocomial infections with significant morbidity and mortality. While the function of lytic transglycosylases (LTs) in relation to cell division, biofilm formation, and antibiotic resistance has been determined for several bacteria, their role in S. aureus remains largely unknown. The only known LTs in S. aureus are immunodominant staphylococcal antigen A (IsaA) and Staphylococcus epidermidis D protein (SceD). Our study demonstrates that, in a strain of methicillin-resistant S. aureus (MRSA), IsaA and SceD contribute differently to biofilm formation and β-lactam resistance. Deletion of isaA, but not sceD, led to decreased biofilm formation. Additionally, in isaA-deleted strains, β-lactam resistance was significantly decreased compared to that of wild-type strains. Plasmid-based expression of mecA, a major determinant of β-lactam resistance in MRSA, in an isaA-deleted strain did not restore β-lactam resistance, demonstrating that the β-lactam susceptibility phenotype is exhibited by isaA mutant regardless of the production level of PBP2a. Overall, our results suggest that IsaA is a potential therapeutic target for MRSA infections.
Elita Jauneikaite, Tricia Ferguson, Mia Mosavie, Joanne L. Fallowfield, Trish Davey, Neil Thorpe, Adrian Allsopp, Anneliese M. Shaw, Dominic Fudge, Matthew K. O’Shea, Duncan Wilson, Marina Morgan, Bruno Pichon, Angela M. Kearns, Shiranee Sriskandan, Lucy E. Lamb
Skin and soft tissue infections (SSTIs) are a serious health issue for military personnel. Of particular importance are those caused by MRSA and PVL-positive S. aureus (PVL-SA), as they have been associated with outbreaks of SSTIs. A prospective observational study was conducted in Royal Marines recruits to investigate the prevalence of PVL-SA carriage and any association with SSTIs.
Goering, R. V., Swartzendruber, E. A., Obradovich, A. E., Tickler, I. A., Tenover, F. C.
Staphylococcus aureus strains that possess a mecA gene but are phenotypically susceptible to oxacillin and cefoxitin (OS-MRSA) have been recognized for over a decade and are a challenge for diagnostic laboratories. The mechanisms underlying the discrepancy vary from isolate to isolate. We characterized seven OS-MRSA clinical isolates of six different spa types from six different states by whole genome sequencing (WGS) to identify the nucleotide sequence changes leading to the OS-MRSA phenotype. The results demonstrated that oxacillin susceptibility was associated with mutations in regions of nucleotide repeats within mecA. Subinhibitory antibiotic exposure selected for secondary mecA mutations that restored oxacillin resistance. Thus, strains of S. aureus that contain mecA but are phenotypically susceptible can become resistant after antibiotic exposure, which may result in treatment failure. OS-MRSA warrant follow-up susceptibility testing to insure detection of resistant revertants.
Ceballos, S., Kim, C., Qian, Y., Mobashery, S., Chang, M., Torres, C.
The in vitro activities of five quinazolinone antibacterials, compounds Q1-Q5, were tested against 210 strains of methicillin-resistant Staphylococcus aureus (MRSA). The MIC50/MIC90 values (both in μg/ml) were as follows: Q1 (0.5/2), Q2 (1/4), Q3 (2/4), Q4 (0.06/0.25) and Q5 (0.125/0.5). Several strains with high MIC values for some of these compounds (from 8 to >32 μg/ml) exhibited amino-acid changes in the penicillin-binding proteins, which are targeted by these antibacterials.
Dafna Yahav, Maria Abbas, Laila Nassar, Alia Ghrayeb, Daniel Kurnik, Daniel Shepshelovich, Leonard Leibovici, Mical Paul
by Dafna Yahav, Maria Abbas, Laila Nassar, Alia Ghrayeb, Daniel Kurnik, Daniel Shepshelovich, Leonard Leibovici, Mical Paul
Introduction Current guidelines recommend maintaining vancomycin trough concentrations between 15–20 mg/L for serious methicillin resistant staphylococcus aureus (MRSA) infections. This recommendation is based on limited evidence. Methods A retrospective study including patients with vancomycin susceptible MRSA infections (MIC< = 2 mg/L), treated with vancomycin. We compared outcomes among patients attaining high (> = 15mg/L) vs low ( = 15 mg/L and clinical outcomes in patients with MRSA infections. In patients with MRSA pneumonia, vancomycin levels > = 15 mg/L were associated with higher clinical success rates. Further larger cohort studies are needed to define optimal vancomycin levels according to the site of infection.
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