scholarly journals Nonredundant Roles of Interleukin-17A (IL-17A) and IL-22 in Murine Host Defense against Cutaneous and Hematogenous Infection Due to Methicillin-Resistant Staphylococcus aureus

2015 ◽  
Vol 83 (11) ◽  
pp. 4427-4437 ◽  
Author(s):  
Liana C. Chan ◽  
Siyang Chaili ◽  
Scott G. Filler ◽  
Kevin Barr ◽  
Huiyuan Wang ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
T Cell ◽  
Host Defense ◽  
Neutralizing Antibodies ◽  
Neutrophil Infiltration ◽  
Renal Tissue ◽  
Methicillin Resistant ◽  
Content Type ◽  
Interleukin 17A ◽  
Mrsa Infection

ABSTRACTStaphylococcus aureusis the leading cause of skin and skin structure infections (SSSI) in humans. Moreover, the high frequency of recurring SSSI due toS. aureus, particularly methicillin-resistantS. aureus(MRSA) strains, suggests that infection induces suboptimal anamnestic defenses. The present study addresses the hypothesis that interleukin-17A (IL-17A) and IL-22 play distinct roles in immunity to cutaneous and invasive MRSA infection in a mouse model of SSSI. Mice were treated with specific neutralizing antibodies against IL-17A and/or IL-22 and infected with MRSA, after which the severity of infection and host immune response were determined. Neutralization of either IL-17A or IL-22 reduced T cell and neutrophil infiltration and host defense peptide elaboration in lesions. These events corresponded with increased abscess severity, MRSA viability, and CFU density in skin. Interestingly, combined inhibition of IL-17A and IL-22 did not worsen abscesses but did increase gamma interferon (IFN-γ) expression at these sites. The inhibition of IL-22 led to a reduction in IL-17A expression, but not vice versa. These results suggest that the expression of IL-17A is at least partially dependent on IL-22 in this model. Inhibition of IL-17A but not IL-22 led to hematogenous dissemination to kidneys, which correlated with decreased T cell infiltration in renal tissue. Collectively, these findings indicate that IL-17A and IL-22 have complementary but nonredundant roles in host defense against cutaneous versus hematogenous infection. These insights may support targeted immune enhancement or other novel approaches to address the challenge of MRSA infection.

scholarly journals Innate Immune Memory Contributes to Host Defense against Recurrent Skin and Skin Structure Infections Caused by Methicillin-Resistant Staphylococcus aureus

2016 ◽  
Vol 85 (2) ◽  
Author(s):  
Liana C. Chan ◽  
Siyang Chaili ◽  
Scott G. Filler ◽  
Lloyd S. Miller ◽  
Norma V. Solis ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Host Defense ◽  
Protective Efficacy ◽  
Innate Immune ◽  
Immune Memory ◽  
Wild Type ◽  
Methicillin Resistant ◽  
Content Type ◽  
Skin Structure ◽  
Mrsa Infection

ABSTRACT Staphylococcus aureus is the leading cause of skin and skin structure infections (SSSI). The high frequency of recurring SSSI due to S. aureus, including methicillin-resistant S. aureus (MRSA) strains, despite high titers of specific antibodies and circulating T cells, implies that traditional adaptive immunity imparts incomplete protection. We hypothesized that innate immune memory contributes to the protective host defense against recurring MRSA infection. To test this hypothesis, SSSI was induced in wild-type and rag1 −/− mice in the BALB/c and C57BL/6 backgrounds. Prior infection (priming) of wild-type and rag1 −/− mice of either background afforded protection against repeat infection, as evidenced by reduced abscess severities and decreased CFU densities compared to those in naive controls. Interestingly, protection was greater on the previously infected flank than on the naive flank for wild-type and rag1 −/− mice. For wild-type mice, protective efficacy corresponded to increased infiltration of neutrophils (polymorphonuclear leukocytes [PMN]), macrophages (MΦ), Langerin+ dendritic cells (LDC), and natural killer (NK) cells. Protection was associated with the induction of interleukin-17A (IL-17A), IL-22, and gamma interferon (IFN-γ) as well as the antimicrobial peptides CRAMP and mβD-3. Priming also protected rag1 −/− mice against recurring SSSI, with increased MΦ and LDC infiltration and induction of IL-22, CRAMP, and mβD-3. These findings suggest that innate immune memory, mediated by specific cellular and molecular programs, likely contributes to the localized host defense in recurrent MRSA SSSI. These insights support the development of targeted immunotherapeutic strategies to address the challenge of MRSA infection.

scholarly journals Daptomycin plus Fosfomycin, a Synergistic Combination in Experimental Implant-Associated Osteomyelitis Due to Methicillin-Resistant Staphylococcus aureus in Rats

2014 ◽  
Vol 59 (2) ◽  
pp. 859-863 ◽  
Author(s):  
Tilman Lingscheid ◽  
Wolfgang Poeppl ◽  
Dominik Bernitzky ◽  
Luzia Veletzky ◽  
Manuel Kussmann ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Once Daily ◽  
Methicillin Resistant ◽  
Bacterial Counts ◽  
Content Type ◽  
Bacterial Cultures ◽  
Development Of Resistance ◽  
Bacterial Inoculum ◽  
Titanium Wire ◽  
Mrsa Infection

ABSTRACTThe aim of this study was to evaluate the combination of daptomycin and fosfomycin in experimental chronic implant-associated osteomyelitis due to methicillin-resistantStaphylococcus aureus(MRSA). Infection was induced in the tibiae of rats by the insertion of a bacterial inoculum (1 to 5 × 108CFU/ml) of a clinical MRSA isolate and a titanium wire. Four weeks after infection, each animal was assigned to a treatment group: daptomycin monotherapy at 60 mg/kg of body weight once daily (n= 10), fosfomycin monotherapy at 40 mg/kg once daily (n= 10), or daptomycin and fosfomycin combined at 60 mg/kg and 40 mg/kg, respectively, once daily (n= 9). Ten animals were left untreated. After a 3-week treatment period, the animals were euthanized, and the infected tibiae and implants were processed for quantitative bacterial cultures. The bacterial cultures from bones were positive for MRSA in all animals in the untreated group, the daptomycin group, and the fosfomycin group, with median bacterial counts of 2.34 × 106CFU/g bone, 1.57 × 106CFU/g bone, and 3.48 × 102CFU/g bone, respectively. In the daptomycin-fosfomycin group, 6 out of 9 animals were positive for MRSA, with a median count of 7.92 CFU/g bone. Bacterial cultures derived from the titanium wires were negative in the fosfomycin- and daptomycin-fosfomycin-treated groups. Based on bacterial counts in bones, treatment with daptomycin-fosfomycin was statistically significantly superior to all that of the other groups (P≤ 0.003). Fosfomycin was superior to daptomycin and no treatment (P< 0.0001). No development of resistance was observed in any treatment arm. The combination of daptomycin and fosfomycin demonstrated synergism against MRSA in experimental implant-associated osteomyelitis.

scholarly journals In VitroPharmacodynamics of Human Simulated Exposures of Ceftaroline and Daptomycin against MRSA, hVISA, and VISA with and without Prior Vancomycin Exposure

2013 ◽  
Vol 58 (2) ◽  
pp. 672-677 ◽  
Author(s):  
Amira A. Bhalodi ◽  
Mao Hagihara ◽  
David P. Nicolau ◽  
Joseph L. Kuti
Keyword(s):  
Staphylococcus Aureus ◽  
Body Weight ◽  
Sequential Therapy ◽  
Free Drug ◽  
Pharmacodynamic Model ◽  
Prior Exposure ◽  
Methicillin Resistant ◽  
Content Type ◽  
Mrsa Infection

ABSTRACTThe effects of prior vancomycin exposure on ceftaroline and daptomycin therapy against methicillin-resistantStaphylococcus aureus(MRSA) have not been widely studied. Humanized free-drug exposures of vancomycin at 1 g every 12 h (q12h), ceftaroline at 600 mg q12h, and daptomycin at 10 mg/kg of body weight q24h were simulated in a 96-hin vitropharmacodynamic model against three MRSA isolates, including one heteroresistant vancomycin-intermediateS. aureus(hVISA) isolate and one VISA isolate. A total of five regimens were tested: vancomycin, ceftaroline, and daptomycin alone for the entire 96 h, and then sequential therapy with vancomycin for 48 h followed by ceftaroline or daptomycin for 48 h. Microbiological responses were measured by the changes in log10CFU during 96 h from baseline. Control isolates grew to 9.16 ± 0.32, 9.13 ± 0.14, and 8.69 ± 0.28 log10CFU for MRSA, hVISA, and VISA, respectively. Vancomycin initially achieved ≥3 log10CFU reductions against the MRSA and hVISA isolates, followed by regrowth beginning at 48 h; minimal activity was observed against VISA. The change in 96-h log10CFU was largest for sequential therapy with vancomycin followed by ceftaroline (−5.22 ± 1.2,P= 0.010 versus ceftaroline) and for sequential therapy with vancomycin followed by ceftaroline (−3.60 ± 0.6,P= 0.037 versus daptomycin), compared with daptomycin (−2.24 ± 1.0), vancomycin (−1.40 ± 1.8), and sequential therapy with vancomycin followed by daptomycin (−1.32 ± 1.0,P> 0.5 for the last three regimens). Prior exposure of vancomycin at 1 g q12h reduced the initial microbiological response of daptomycin, particularly for hVISA and VISA isolates, but did not affect the response of ceftaroline. In the scenario of poor vancomycin response for high-inoculum MRSA infection, a ceftaroline-containing regimen may be preferred.

scholarly journals Comparative Genomics of Vancomycin-Resistant Staphylococcus aureus Strains and Their Positions within the Clade Most Commonly Associated with Methicillin-Resistant S. aureus Hospital-Acquired Infection in the United States

mBio ◽  
2012 ◽  
Vol 3 (3) ◽  
Author(s):  
Veronica N. Kos ◽  
Christopher A. Desjardins ◽  
Allison Griggs ◽  
Gustavo Cerqueira ◽  
Andries Van Tonder ◽  
...  
Keyword(s):  
United States ◽  
Staphylococcus Aureus ◽  
The United States ◽  
Methicillin Resistant ◽  
Content Type ◽  
Mrsa Infection ◽  
Vancomycin Resistant ◽  
Foreign Dna ◽  
Mrsa Strains ◽  
Hospital Acquired

ABSTRACTMethicillin-resistantStaphylococcus aureus(MRSA) strains are leading causes of hospital-acquired infections in the United States, and clonal cluster 5 (CC5) is the predominant lineage responsible for these infections. Since 2002, there have been 12 cases of vancomycin-resistantS. aureus(VRSA) infection in the United States—all CC5 strains. To understand this genetic background and what distinguishes it from other lineages, we generated and analyzed high-quality draft genome sequences for all available VRSA strains. Sequence comparisons show unambiguously that each strain independently acquired Tn1546and that all VRSA strains last shared a common ancestor over 50 years ago, well before the occurrence of vancomycin resistance in this species. In contrast to existing hypotheses on what predisposes this lineage to acquire Tn1546, the barrier posed by restriction systems appears to be intact in most VRSA strains. However, VRSA (and other CC5) strains were found to possess a constellation of traits that appears to be optimized for proliferation in precisely the types of polymicrobic infection where transfer could occur. They lack a bacteriocin operon that would be predicted to limit the occurrence of non-CC5 strains in mixed infection and harbor a cluster of unique superantigens and lipoproteins to confound host immunity. A frameshift indprA, which in other microbes influences uptake of foreign DNA, may also make this lineage conducive to foreign DNA acquisition.IMPORTANCEInvasive methicillin-resistantStaphylococcus aureus(MRSA) infection now ranks among the leading causes of death in the United States. Vancomycin is a key last-line bactericidal drug for treating these infections. However, since 2002, vancomycin resistance has entered this species. Of the now 12 cases of vancomycin-resistantS. aureus(VRSA), each was believed to represent a new acquisition of the vancomycin-resistant transposon Tn1546from enterococcal donors. All acquisitions of Tn1546so far have occurred in MRSA strains of the clonal cluster 5 genetic background, the most common hospital lineage causing hospital-acquired MRSA infection. To understand the nature of these strains, we determined and examined the nucleotide sequences of the genomes of all available VRSA. Genome comparison identified candidate features that position strains of this lineage well for acquiring resistance to antibiotics in mixed infection.

scholarly journals Chlorhexidine and Mupirocin Susceptibility of Methicillin-Resistant Staphylococcus aureus Isolates in the REDUCE-MRSA Trial

2016 ◽  
Vol 54 (11) ◽  
pp. 2735-2742 ◽  
Author(s):  
Mary K. Hayden ◽  
Karen Lolans ◽  
Katherine Haffenreffer ◽  
Taliser R. Avery ◽  
Ken Kleinman ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Cluster Randomized Trial ◽  
Confidence Limits ◽  
Methicillin Resistant ◽  
Content Type ◽  
Mrsa Infection ◽  
Mupirocin Resistance ◽  
Cluster Randomized ◽  
High Level

Whether targeted or universal decolonization strategies for the control of methicillin-resistant Staphylococcus aureus (MRSA) select for resistance to decolonizing agents is unresolved. The REDUCE-MRSA trial (ClinicalTrials registration no. NCT00980980) provided an opportunity to investigate this question. REDUCE-MRSA was a 3-arm, cluster-randomized trial of either screening and isolation without decolonization, targeted decolonization with chlorhexidine and mupirocin, or universal decolonization without screening to prevent MRSA infection in intensive-care unit (ICU) patients. Isolates from the baseline and intervention periods were collected and tested for susceptibility to chlorhexidine gluconate (CHG) by microtiter dilution; mupirocin susceptibility was tested by Etest. The presence of the qacA or qacB gene was determined by PCR and DNA sequence analysis. A total of 3,173 isolates were analyzed; 2 were nonsusceptible to CHG (MICs, 8 μg/ml), and 5/814 (0.6%) carried qacA or qacB . At baseline, 7.1% of MRSA isolates expressed low-level mupirocin resistance, and 7.5% expressed high-level mupirocin resistance. In a mixed-effects generalized logistic regression model, the odds of mupirocin resistance among clinical MRSA isolates or MRSA isolates acquired in an ICU in intervention versus baseline periods did not differ across arms, although estimates were imprecise due to small numbers. Reduced susceptibility to chlorhexidine and carriage of qacA or qacB were rare among MRSA isolates in the REDUCE-MRSA trial. The odds of mupirocin resistance were no different in the intervention versus baseline periods across arms, but the confidence limits were broad, and the results should be interpreted with caution.

scholarly journals Heterogeneity ofmprFSequences in Methicillin-Resistant Staphylococcus aureus Clinical Isolates: Role in Cross-Resistance between Daptomycin and Host Defense Antimicrobial Peptides

2014 ◽  
Vol 58 (12) ◽  
pp. 7462-7467 ◽  
Author(s):  
Arnold S. Bayer ◽  
Nagendra N. Mishra ◽  
George Sakoulas ◽  
Poochit Nonejuie ◽  
Cynthia C. Nast ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Host Defense ◽  
Hot Spot ◽  
Cross Resistance ◽  
Phospholipid Content ◽  
Nucleotide Polymorphisms ◽  
Gain Of Function ◽  
Host Defense Peptides ◽  
Methicillin Resistant ◽  
Content Type

ABSTRACTOver the past several years, single-nucleotide polymorphisms (SNPs) within themprFopen reading frame (ORF) have been proposed to be associated with a gain-of-function phenotype in terms of daptomycin (DAP) nonsusceptibility (referred to as daptomycin resistance [DAP-R] herein for ease of presentation) inStaphylococcus aureus. We investigated the frequencies of SNPs within themprFORF and the relationships of such SNPs to cross-resistance between DAP and cationic host defense peptides (HDPs). Thirty-five well-characterized, unique DAP-susceptible (DAP-S) and DAP-R methicillin-resistantS. aureus(MRSA) isolates of the clonal complex 5 genotype were used. In addition tomprFSNPs and DAP-HDP cross-resistance, several other key genotypic and phenotypic metrics often associated with DAP-R were delineated, as follows: (i)mprFexpression, (ii) membrane phospholipid content, (iii) positive surface charge, (iv) DAP binding, and (v) cell wall thickness profiles. A number of DAP-S strains (MICs of ≤1 μg/ml) exhibitedmprFSNPs, occasionally with high-levelmprFsequence variation from the genotype reference strain. However, none of these SNPs were localized to well-chronicledmprFhot spot locations associated with DAP-R inS. aureus. In contrast, all 8 DAP-R isolates demonstrated SNPs within such knownmprFhot spots. Moreover, only the DAP-R strains showed MprF gain-of-function phenotypes, enhancedmprFexpression, higher survival against two prototypical HDPs, and reduced DAP binding. Although a heterogenous array ofmprFSNPs were often found in DAP-S strains, only selected hot spot SNPs, combined with concurrentmprFdysregulation, were associated with the DAP-R phenotype.

scholarly journals Efficacy of Skin and Nasal Povidone-Iodine Preparation against Mupirocin-Resistant Methicillin-Resistant Staphylococcus aureus and S. aureus within the Anterior Nares

2015 ◽  
Vol 59 (5) ◽  
pp. 2765-2773 ◽  
Author(s):  
Michele J. Anderson ◽  
Maren L. David ◽  
Matt Scholz ◽  
Sally J. Bull ◽  
Dan Morse ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Human Skin ◽  
Povidone Iodine ◽  
Human Subjects ◽  
Surgical Site Infections ◽  
Attractive Alternative ◽  
Methicillin Resistant ◽  
Content Type ◽  
Nasal Swabs ◽  
Mrsa Infection

ABSTRACTMupirocin decolonization of nasalStaphylococcus aureusprior to surgery decreases surgical-site infections; however, treatment requires 5 days, compliance is low, and resistance occurs. In 2010, 3M Company introduced povidone-iodine (PVP-I)-based skin and nasal antiseptic (Skin and Nasal Prep [SNP]). SNP has rapid, broad-spectrum antimicrobial activity. We tested SNP's efficacy using full-thickness tissue (porcine mucosal [PM] and human skin) explant models and human subjects. Prior to or following infection with methicillin-resistantStaphylococcus aureus(MRSA) (mupirocin sensitive and resistant), explants were treated with Betadine ophthalmic preparation (Bet), SNP, or mupirocin (Bactroban nasal ointment [BN]) or left untreated. One hour posttreatment, explants were washed with phosphate-buffered saline (PBS) plus 2% mucin. One, 6, or 12 h later, bacteria were recovered and enumerated. Alternatively, following baseline sampling, human subjects applied two consecutive applications of SNP or saline to their anterior nares. One, 6, and 12 h after application of the preparation (postprep), nasal swabs were obtained, andS. aureuswas enumerated. We observed that treatment of infected PM or human skin explants with SNP resulted in >2.0 log10CFU reduction in MRSA, regardless of mupirocin sensitivity, which was significantly different from the values for BN- and Bet-treated explants and untreated controls 1 h, 6 h, and 12 h after being washed with PBS plus mucin. Swabbing the anterior nares of human subjects with SNP significantly reduced residentS. aureuscompared to saline 1, 6, and 12 h postprep. Finally, pretreatment of PM explants with SNP, followed by a mucin rinse prior to infection, completely prevented MRSA infection. We conclude that SNP may be an attractive alternative for reducing the bioburden of anterior nares prior to surgery.

scholarly journals Commercially Distributed Meat as a Potential Vehicle for Community-Acquired Methicillin-Resistant Staphylococcus aureus

2012 ◽  
Vol 78 (8) ◽  
pp. 2797-2802 ◽  
Author(s):  
Kikuyo Ogata ◽  
Hiroshi Narimatsu ◽  
Masahiro Suzuki ◽  
Wataru Higuchi ◽  
Tatsuo Yamamoto ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Drug Susceptibility ◽  
Methicillin Resistant ◽  
Content Type ◽  
Reading Frame ◽  
Type Iv ◽  
Mrsa Infection ◽  
Stool Samples ◽  
Mrsa Strains ◽  
Meat Samples

ABSTRACTThe incidence of community-acquired methicillin-resistantStaphylococcus aureus(CA-MRSA) infection has been increasing; however, the sources of infection remain unclear. Therefore, we investigated the involvement of meat as a possible mediator of CA-MRSA infection. We examined the distribution of MRSA strains in commercially distributed raw meat samples (n= 197) and diarrheal stool samples of outpatients (n= 1,287) that were collected in Oita Prefecture, Japan, between 2003 and 2009 for routine legal inspections. Fourteen MRSA strains were isolated from three meat and 11 stool samples. Among these, seven isolates from three meat and four stool samples exhibited the same epidemiological marker profiles [coagulase type III, staphylococcal enterotoxin C, staphylococcal chromosomal cassettemec(SCCmec) type IV, ST8,spatype 606 (t1767), and toxic shock syndrome toxin-1 (TSST-1) producing type]. Furthermore, of the seven strains, three isolates from two meat samples and one stool sample collected in 2007 exhibited completely identical characteristics with respect to phage open reading frame (ORF) typing, pulsed-field gel electrophoresis, and drug susceptibility profiles. The results suggest that commercially distributed meat could play a role in the prevalence of CA-MRSA in the community.

scholarly journals Methicillin-Resistant Staphylococcus aureus spa Type t002 Outbreak in Horses and Staff at a Veterinary Teaching Hospital after Its Presumed Introduction by a Veterinarian

2015 ◽  
Vol 53 (9) ◽  
pp. 2827-2831 ◽  
Author(s):  
Amir Steinman ◽  
Samira Masarwa ◽  
Sharon Tirosh-Levy ◽  
Dan Gleser ◽  
Gal Kelmer ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Teaching Hospital ◽  
Large Animal ◽  
Prevalence Survey ◽  
Methicillin Resistant ◽  
Content Type ◽  
Staff Members ◽  
Cross Transmission ◽  
Mrsa Infection ◽  
Mrsa Strains

Methicillin-resistantStaphylococcus aureus(MRSA) infection and colonization, involving MRSA strains which differ from common human health care-associated clones, have become serious emerging conditions in equine veterinary hospitals. In 2010, MRSAspatype t535 caused an outbreak involving both horses and personnel in a veterinary teaching hospital in Israel. Since then, surveillance continued, and occasional MRSA isolation occurred. Two years later, MRSA of anotherspatype, t002, was isolated from a veterinarian and, 3 weeks later, from a horse. The appearance ofspatype t002, a common clone in human medicine in Israel, among both personnel and horses, prompted a point-prevalence survey of hospital personnel and hospitalized horses. Fifty-nine staff members (n= 16 equine;n= 43, other) and 14 horses were screened. Ten of 59 staff members (16.9%) and 7 of 14 horses (50%) were MRSA carriers. Among the staff, 44% of large animal department (LAD) personnel, compared with only 7% of non-LAD personnel, were carriers. Isolates from all horses and from 9 of 10 personnel were found to be of MRSAspatype t002. This clone was later isolated from an infected postoperative wound in a hospitalized horse. Measures were taken to contain transmission between horses and personnel, as was done in the previous outbreak, resulting in reduction of transmission and, finally, cessation of cross-transmission between horses and personnel.

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