Associations of pathogen‐specific and host‐specific characteristics with disease outcome in patients with Staphylococcus aureus bacteremic pneumonia

Abstract

Objective To understand the relationships of Staphylococcus aureus (SA) bacteremic pneumonia (SABP) outcome with patient‐specific and SA‐specific variables. Methods We analysed SA bloodstream isolates and matching sera in SABP patients by sequencing SA isolates (n = 50) and measuring in vitro AT production, haemolytic activity and expression of ClfA and ClfB. Controls were sera from gram‐negative bacteremia patients with or without pneumonia and uninfected subjects. Levels of IgGs, IgMs and neutralizing antibodies (NAbs) against SA antigens were quantified and analysed by one‐way ANOVA. Associations of patient outcomes with patient variables, antibody levels and isolate characteristics were evaluated by univariate and multivariate logistic regression analyses. Results SABP patients had higher levels of IgGs against eight virulence factors and anti‐alpha toxin (AT) NAbs than uninfected controls. Levels of IgG against AT and IgMs against ClfA, FnbpA and SdrC were higher in clinically cured SABP patients than in clinical failures. Anti‐LukAB NAb levels were elevated in all cohorts. Increased odds of cure correlated with higher haemolytic activity of SA strains, longer time between surgery and bacteremia (> 30 days), longer duration of antibiotic therapy, lower acute physiology and total APACHE II scores, lack of persistent fever for > 72 h and higher levels of antibodies against AT (IgG), ClfA (IgM), FnbpA (IgM) and SdrC (IgM). Discussion Limitations included the cross‐sectional observational nature of the study, small sample size and inability to measure antibody levels against all SA virulence factors. Conclusion Our results suggest that SABP patients may benefit from immunotherapy targeting multiple SA antigens.

Exploring Virulence Factors and Alternative Therapies against Staphylococcus aureus Pneumonia

“…Despite the specific pathways still being unclear, the importance of Hla in biofilm-related S. aureus pathogenesis was demonstrated in different models using human skin and porcine vaginal mucosal tissue [69,73], as well as using transcriptomic approaches [120]. The generation of high titers of natural antibodies (Abs) against Hla following invasive S. aureus infections, including pneumonia, further confirms these findings [103,121,122].…”

“…In a recent study by Sharma-Kuinkel et al, patients with clinically cured SAP had higher IgM titers against FnBPA compared to patients with treatment failure, suggesting a protective role for anti-FnBPA Abs [ 103 ]. Based on this and other data, FnBPA emerged as an interesting virulence target in S. aureus research.…”

Dissecting the Human Response to Staphylococcus aureus Systemic Infections

“…The responses against Hla have been previously reported and high antibody titers against the toxin are generated following S. aureus invasive infections, including bacteremia and pneumonia ( 23 , 24 ). Similarly, LukAB response is frequent in invasive disease and children with diagnosis of S. aureus disease generate high serum anti-LukAB titers early in the course of disease ( 25 ), leading to the evidence that LukAB antibodies might be useful in the diagnosis of invasive bacterial infections ( 26 ).…”

Epidemiological and Clinical Evidence for the Role of Toxins in S. aureus Human Disease

“…Data regarding the role of Hla in the pathogenesis of S. aureus infections in humans are less abundant, although evidence suggests that the toxin is at least expressed in the setting of human disease. For example, numerous studies have identified a robust and neutralizing antibody response to α-toxin [ 14 , 15 , 16 ] following sepsis or pneumonia. A pediatric study measuring antibody levels in 235 children found that antibody titers to Hla from convalescent sera correlated with protection against subsequent S. aureus infection up to a year later [ 17 ].…”

“…The presence of LukAB antibodies has also been associated with specific diseases, such as cystic fibrosis, where an increase in LukA IgG titers in serum during pulmonary exacerbation with S. aureus infection has been reported [ 53 ]. Another study found an increase in anti-LukAB IgG-neutralizing titers in patients with bacteremic pneumonia [ 15 ]. In addition, functional monoclonal antibodies targeting LukAB have been isolated, using both yeast display and human hybridoma technology.…”