Lower Antibody Levels to Staphylococcus aureus Exotoxins Are Associated With Sepsis in Hospitalized Adults With Invasive S. aureus Infections

Adhikari, Rajan P.; Ajao, Adebola; Aman, M. Javad; Karaüzüm, Hatice; Sarwar, Jawad; Lydecker, Alison D.; Johnson, J. Kristie; Nguyen, Chinh; Chen, Wilbur H.; Roghmann, Mary-Claire

doi:10.1093/infdis/jis462

Cited by 123 publications

(124 citation statements)

References 44 publications

(42 reference statements)

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“…Especially in the community, the frequency of infections caused by MRSA has increased in the last decade (22). It is believed that the prevalence of MRSA carriage increases in a healthy community and, therefore, the surveillance of MSSA and MRSA in the nasal carriage has been investigated in healthy individuals.…”

Section: Discussionmentioning

confidence: 99%

Detection of Methicillin Resistance and Various Virulence Factors in Staphylococcus aureus Strains Isolated from Nasal Carriers

Dağı¹,

Fındık²,

Demırel³

et al. 2015

Balkan Med J

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Staphylococcus aureus can be found as a commensal on the skin and nasal flora, and may cause local, severe, and invasive infections, such as bacteremia or pneumonia (1). The anterior nostrils represent the most common area for colonization of staphylococci; in fact, longitudinal studies have shown that ~50% of individuals are S. aureus nasal carriers (2,3). Curiously, nasal colonization has been identified as a major risk factor for the development of community-acquired and nosocomial S. aureus infections (4,5).The capacity of S. aureus to acquire antibiotic resistance genes is important. Methicillin-resistant S. aureus (MRSA) isolates have been subsequently reported in hospital and community settings worldwide. The increasing prevalence of MRSA in the hospital acquired (HA-MRSA) and the community acquired (CA-MRSA) is threatening. By definition, all MRSA (carrying mecA gene) species are resistant to betalactam antibiotics. In addition, MRSA isolates can obtain other resistance determinants. Nevertheless, nowadays, S. aureus colonizer strains are mostly methicillin-susceptible ones (MSSA) (3). Although some studies including healthy people have shown that the prevalence of S. aureus and the Background: Staphylococus aureus can be found as a commensal on skin and nasal flora or it may cause local and invasive infections. S. aureus has a large number of virulence factors. Aims: To investigate the methicillin resistance and frequency of various virulence factors in S. aureus nasal isolates. Study Design: Descriptive study. Methods: Nasal samples collected from university students were cultured in media. S. aureus was identified by conventional methods and the Staphyloslide latex test (Becton Dickinson, Sparks, USA). Antibiotic susceptibility tests were conducted, and the methicillin resistance was determined. The mecA, nuc, pvl and staphylococcal toxin genes were examined by polymerase chain reaction (PCR). Results: S. aureus was isolated in 104 of 600 (17.3%) nasal samples. In total, 101 (97.1%) S. aureus isolates were methicillin-sensitive and the remaining 3 (2.9%) were methicillin-resistant. Furthermore, all but five isolates carried at least one staphylococcal enterotoxin gene, with seg being predominant. The tst and eta genes were determined in 29 (27.9%), and 3 (2.9%) isolates, respectively. None of the S. aureus isolates harbored see, etb, and pvl genes. Conclusion: A moderate rate of S. aureus carriage and low frequency of MRSA were detected in healthy students. S. aureus isolates had a high prevalence of staphylococcal enterotoxin genes and the tst gene. In this study, a large number of virulence factors were examined in S. aureus nasal isolates, and the data obtained from this study can be used for monitoring the prevalence of virulence genes in S. aureus strains isolated from nasal carriers.

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Section: Discussionmentioning

confidence: 99%

Detection of Methicillin Resistance and Various Virulence Factors in Staphylococcus aureus Strains Isolated from Nasal Carriers

Dağı¹,

Fındık²,

Demırel³

et al. 2015

Balkan Med J

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“…High antibody levels to alpha-toxin have been described in S. aureus subjects with various dermatoses and especially in atopic dermatitis subjects (50). A more recent study evaluating the risk of sepsis in S. aureus-infected patients showed that the incidence of sepsis was significantly lower in patients with higher IgG levels against alpha-toxin, Hld, Panton-Valentine leukocidin, SEC-1, and PSM-␣3 (36). Data suggesting that high levels of anti-alpha-toxin antibodies are protective in preventing S. aureus endocarditis were reported from a study by Ruotsalainen et al (48).…”

Section: Figmentioning

confidence: 99%

“…Twelve distinct alpha-toxin sequence types were identified from the 197 hla-positive isolates, and MEDI4893 neutralized alpha-toxin produced by all 12 different variants. Based on these observations, the correlation of higher anti-alpha-toxin antibody levels to better clinical outcomes in epidemiological studies (36,48,51) and the efficacy of alpha-toxin MAbs or vaccines in animal models (27,(32)(33)(34), we have initiated a phase 2 clinical trial with MEDI4893 to prevent ventilator-associated S. aureus pneumonia. Further studies are under way to verify these observations among S. aureus pneumonia patients.…”

Section: Figmentioning

confidence: 99%

“…Antibodies against alpha-toxin were both necessary and sufficient for protection against soft tissue infection and were inversely associated with bacterial counts (32) and had a protective role in keratitis (35). Also, a recent report suggested that higher antibody (Ab) levels against alpha-toxin have a protective role against sepsis in patients with invasive S. aureus infections (36). Despite these important insights, the complex interplay between alpha-toxin production by bloodstream S. aureus isolates, anti-alpha-toxin antibody production by bacteremic patients, and the clinical outcomes for such patients is incompletely understood.…”

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confidence: 99%

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Characterization of Alpha-Toxin hla Gene Variants, Alpha-Toxin Expression Levels, and Levels of Antibody to Alpha-Toxin in Hemodialysis and Postsurgical Patients with Staphylococcus aureus Bacteremia

Sharma-Kuinkel

Wu²,

Tabor³

et al. 2015

J Clin Microbiol

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c Alpha-toxin is a major Staphylococcus aureus virulence factor. This study evaluated potential relationships between in vitro alpha-toxin expression of S. aureus bloodstream isolates, anti-alpha-toxin antibody in serum of patients with S. aureus bacteremia (SAB), and clinical outcomes in 100 hemodialysis and 100 postsurgical SAB patients. Isolates underwent spa typing and hla sequencing. Serum anti-alpha-toxin IgG and neutralizing antibody levels were measured by using an enzyme-linked immunosorbent assay and a red blood cell (RBC)-based hemolysis neutralization assay. Neutralization of alpha-toxin by an anti-alpha-toxin monoclonal antibody (MAb MEDI4893) was tested in an RBC-based lysis assay. Most isolates encoded hla (197/200; 98.5%) and expressed alpha-toxin (173/200; 86.5%). In vitro alpha-toxin levels were inversely associated with survival (cure, 2.19 g/ml, versus failure, 1.09 g/ml; P < 0.01). Both neutralizing (hemodialysis, 1.26 IU/ml, versus postsurgical, 0.95; P < 0.05) and IgG (hemodialysis, 1.94 IU/ml, versus postsurgical, 1.27; P < 0.05) antibody levels were higher in the hemodialysis population. Antibody levels were also significantly higher in patients infected with alpha-toxin-expressing S. aureus isolates (P < 0.05). Levels of both neutralizing antibodies and IgG were similar among patients who were cured and those not cured (failures). Sequence analysis of hla revealed 12 distinct hla genotypes, and all genotypic variants were susceptible to a neutralizing monoclonal antibody in clinical development (MEDI4893). These data demonstrate that alpha-toxin is highly conserved in clinical S. aureus isolates. Higher in vitro alpha-toxin levels were associated with a positive clinical outcome. Although patients infected with alpha-toxin-producing S. aureus exhibited higher anti-alpha-toxin antibody levels, these levels were not associated with a better clinical outcome in this study. Staphylococcus aureus is a leading cause of bacterial infections (1-4), including skin and soft tissue infections (5), pneumonia (6), bacteremia (7), endocarditis (8-10), and bone and joint infections (11). The risk of invasive S. aureus infections is significantly higher among certain subgroups, including hemodialysisdependent patients and postoperative patients (12-14).These high-risk subpopulations are potential candidates for novel forms of prevention or treatment against invasive S. aureus infections.Alpha-toxin, a ␤-barrel pore-forming exotoxin encoded by hla (15, 16), is a key virulence factor produced by most S. aureus isolates (17, 18). It binds to ADAM10 (the A disintegrin and metalloproteinase domain-containing protein 10) on target cell membranes and then heptamerizes to generate a transmembrane pore, resulting in cell lysis (19). Hyperproduction of alpha-toxin is associated with enhanced virulence in strains of both epidemic (USA300 and USA500) and endemic (ST93) community-associated methicillin-resistant S. aureus (CA-MRSA) isolates (20,21). Studies with a number of animal models have also suggested that al...

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“…24 In observational studies, higher levels of IgG antibody to a-toxin have been associated with reduced risk of sepsis in adult patients with invasive staphylococcal infections. 25 In addition, long-term follow-up of children with invasive S. aureus disease reveals a protective association between anti-a-toxin antibody titers and recurrent infection. 26 PVL is a pore-forming cytotoxin consisting of 2 subunits, LukS-PV and LukF-PV, which cause leukocyte destruction and tissue necrosis.…”

Section: Introductionmentioning

confidence: 99%

Safety and immunogenicity of a recombinant Staphylococcus aureus α-toxoid and a recombinant Panton-Valentine leukocidin subunit, in healthy adults

Landrum

Lalani

Niknian³

et al. 2017

Human Vaccines & Immunotherapeutics

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We conducted a randomized, double-blind, placebo-controlled dose-escalation study in healthy adults to evaluate the safety and immunogenicity of recombinant Staphylococcus aureus candidate vaccine antigens, recombinant a-toxoid (rAT) and a sub-unit of Panton-Valentine leukocidin (rLukS-PV). 176 subjects were enrolled and randomized within 1 of 11 treatment cohorts: monovalent rAT or rLukS-PV dosages of 10, 25, 50, and 100 mg; bivalent rAT:rLukS dosages of 10:10, 25:25, and 50:50 mg; and alum or saline placebo. All subjects were assessed at Days 0, 7, 14, 28, and 84. Subjects in the 50:50 mg bivalent cohort received a second injection on Day 84 and were assessed on Days 98 and 112. Incidence and severity of reactogenicity and adverse events (AEs) were compared. Geometric mean serum concentrations (GMC) and neutralizing activity of anti-rAT and anti-rLukS-PV IgG were assessed. Reactogenicity incidence was significantly higher in vaccine than placebo recipients (77% versus 55%, respectively; p D 0.006). However, 77% of reactogenicity events were mild and 19% were moderate in severity. The AE incidence and severity were similar between the cohorts. All monovalent and bivalent rAT dosages resulted in a significant increase in the anti-rAT IgG and anti-rLukS-PV GMCs between day 0 and 28 compared with placebo, and persisted through Day 84. Exploratory subgroup analyses suggested a higher GMC and neutralizing antibody titers for the 50 mg monovalent or bivalent rAT and rLukS-PV dose as compared to the other doses. No booster effect was observed after administration of the second dose. We conclude that the rAT and rLukS-PV vaccine formulations were well-tolerated and had a favorable immunogenicity profile, producing antibody with neutralizing activity through day 84. There was no benefit observed with a booster dose of the vaccine.

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Lower Antibody Levels to Staphylococcus aureus Exotoxins Are Associated With Sepsis in Hospitalized Adults With Invasive S. aureus Infections

Cited by 123 publications

References 44 publications

Detection of Methicillin Resistance and Various Virulence Factors in Staphylococcus aureus Strains Isolated from Nasal Carriers

Detection of Methicillin Resistance and Various Virulence Factors in Staphylococcus aureus Strains Isolated from Nasal Carriers

Characterization of Alpha-Toxin hla Gene Variants, Alpha-Toxin Expression Levels, and Levels of Antibody to Alpha-Toxin in Hemodialysis and Postsurgical Patients with Staphylococcus aureus Bacteremia

Safety and immunogenicity of a recombinant Staphylococcus aureus α-toxoid and a recombinant Panton-Valentine leukocidin subunit, in healthy adults

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