Staphylococcus aureus (S. aureus) bacteremia is a life-threatening condition with high morbidity and mortality rates. Several studies have addressed the incidence, prevalence, and clinical outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and S. aureus coinfection, but the genomic differences between pandemic and pre-pandemic strains have not been explored. In this study, the Spanish authors used S. aureus isolates to investigate the clinical aspects and genomic characteristics of bacterial strains isolated from patients with bacteremia before and during the COVID-19 pandemic (2014–2022). Comparative genomics analysis of 339 isolates showed adaptation of Staphylococcus aureus to COVID-19 selective pressure.
Understanding the interplay between viral and bacterial infections, including the prevalence and impact of S. aureus in COVID-19 cases, is important for effective patient care and public health measures. S. aureus has been described as a leading cause of secondary infection during the COVID-19 pandemic, significantly increasing patient mortality rates. Interestingly, a previous study employing a computational integrative approach for epitope prediction and identification revealed the molecular similarity between antigenic sites in the SARS-CoV-2 receptor binding domain (RBD) and 54 antigenic determinants of fifteen pathogenic bacteria, parasites, and viruses. The antigenic determinant predicted from Staphylococcus aureus with molecular similarity with SARS-CoV-2 RBD antigens was Enterotoxin A. The author stated that these findings are seriously alarming, as the presence of antigenic determinants that are similar to those found in highly pathogenic microorganisms explains numerous pathophysiological complications in COVID-19, including a deregulated immune response, unleashed or dysregulated cytokine secretion (cytokine storm), and multiple organ failure. https://discovermednews.com/molecular-similarities-between-sars-cov-2-rbd-and-pathogens/
Staphylococcus aureus
About the Study and Results
The study included 339 adult patients diagnosed with S. aureus bloodstream infection between 2014 and 2022. Persistent bacteremia was defined as the presence of positive blood cultures after 72 h of appropriate antibiotic therapy. Only the first episode of S. aureus bacteremia was included in the analysis for each patient. Most patients were male (69.3%), and the mean age was 63.7 ± 19.9 years. 93 patients died (27.4%), and the median time to the patient’s death was 20 days.
The most frequent clinical diagnoses were diabetes (31.6%), the presence of a foreign device (25.4%), ischemic heart disease (17.7%), congestive heart failure (16.5%), solid neoplasm (15.3%), peripheral arteriopathy (12.7%), and chronic obstructive pulmonary disease (10.0%). Most S.aureus infections were nosocomial (56.6%), while 27.4% were community-acquired and 16.0% were healthcare-related. The predominant primary sources of infection were vascular catheters (31.8%), skin infections (18.0%), and pneumonia (9.4%), whereas 30.7% of episodes were of unknown origin.
Antibiotic tests identified resistance to penicillin (86.1%), erythromycin (30.4%), clindamycin (20.9%), ciprofloxacin (16.8%), levofloxacin (15.3%), oxacillin (13.9%), amoxicillin/clavulanic acid (13.6%), gentamicin (10.0%), tetracycline (2.9%), cotrimoxazole (1.5%), linezolid (0.3%), and rifampicin (0.3%).
The multilocus sequence typing software classified S.aureus isolates in 24 different lineages. The major identified lineages were CC30 (19.5%), CC5 (17.1%), CC45 (12.1%), ST398 (8.8%), CC8 (8.8%), CC22 (8.0%), and CC15 (5.9%). 18 isolates could not be classified into a known sequence type. The distribution of lineages remained relatively stable over the years of study.
Methicillin-resistant S. aureus
Changes in molecular characteristics of pandemic S.aureus isolates
200 adult patients were diagnosed with S. aureus bloodstream infection after March 14th, 2020, and 32% tested positive for SARS-CoV-2. Strains isolated from March 14th, 2020 onwards were considered as pandemic clones.
During the COVID-19 pandemic, the number of episodes of S. aureus bacteremia per year increased by 140% (from 28 in the pre-pandemic years to 67 in the pandemic years). Nosocomial infections rose from 69 episodes in the pre-pandemic years to 119 during the pandemic. Specifically, there was an increase in the prevalence of S. aureus bacteremia originating from catheters and surgical sites, methicillin-resistant S. aureus (MRSA) strain infections, and endocarditis cases. The number of community-acquired S. aureus bacteremia was significantly reduced.
During the pandemic, the researchers did not detect emerging S. aureus clones, and the prevalence of lineages throughout the pandemic period was indistinguishable from those before the pandemic. Similarly, core genome phylogenetic analysis did not reveal the presence of emerging sub-lineages within the major lineages during the pandemic years.
However, the genetic differences between pre-pandemic and pandemic strains of S. aureus were significant. The prevalence of strains carrying the clfA and clfB genes, which are MSCRAMMs encoding fibrinogen-binding clumping factors A and B, increased. ClfA is the major virulence factor responsible for S. aureus clumping in blood plasma, and ClfB interacts with cytokeratin 10 and loricrin and facilitates S. aureus infection of the skin. ClfA and ClfB are involved in the aggregation of bacteria and platelets. In contrast, the prevalence of the sdrE gene, which encodes an MSCRAMM that prevents phagocytosis of S. aureus by sequestering human complement factor H (CFH) on the bacterial cell surface, was reduced. The SARS-CoV-2 spike protein has been shown to block CFH, leading to dysregulation of complement on the human cell surface. The presence of clfA, clfB, and sdrE genes in S. aureus co-infecting COVID-19 patients had no impact on the clinical outcome of bacteremia.
Genetic features in pandemic isolates also revealed a higher prevalence of methicillin (mecA) and macrolide (msrA and mphC) resistance genes. It should be noted that macrolides were extensively used as accessory therapy for COVID-19.
Original illustration from study by Sánchez-Osuna M et al. iScience 27, 110402, 2024
According to the authors, these results imply that the prevalence of these genes is increasing across diverse lineages, suggesting a genetic enrichment process rather than the emergence of dominant lineages during the pandemic. This reflects an evolutionary scenario in which specific genes are convergently selected among diverse isolates, regardless of lineage, likely due to selective pressure during the COVID-19 infection.
Conclusion
Comparative genomic analysis of 339 S. aureus isolates from patients with bacteremia highlighted the adaptation of Staphylococcus aureus to COVID-19 selective pressure. Some virulence factors and antibiotic resistance genes were enriched in pandemic S. aureus isolates. The presence of the clfA and clfB genes gave S. aureus an advantage in the context of SARS-CoV-2 coinfection by enhancing fibrinogen binding. As macrolides were extensively used as accessory therapy for COVID-19 patients, the higher prevalence of macrolide resistance genes (msrA and mphC) indicates the evolving nature of S. aureus infections in the COVID-19 pandemic.
According to the authors, these results suggest convergent selection for the presence of these genes in multiple lineages, a widespread phenomenon rather than the emergence of particular lineages.
This study shows that genomics enables the tracking of specific strains and the identification of emerging threats, contributing to infection surveillance and control.
This article was published in iScience.
Journal Reference
Sánchez-Osuna M, Pedrosa M, Bierge P et al. Genomic analysis of Staphylococcus aureus isolates from bacteremia reveals genetic features associated with the COVID-19 pandemic. Iscience 27, 110402, August 16, 2024. https://doi.org/10.1016/j.isci.2024.110402
