Management of Staphylococcus aureus Bacteremia: A Review

Abstract

Importance: Staphylococcus aureus, a gram-positive bacterium, is the leading cause of death from bacteremia worldwide, with a case fatality rate of 15% to 30% and an estimated 300 000 deaths per year.

Observations: Staphylococcus aureus bacteremia causes metastatic infection in more than one-third of cases, including endocarditis (≈12%), septic arthritis (7%), vertebral osteomyelitis (≈4%), spinal epidural abscess, psoas abscess, splenic abscess, septic pulmonary emboli, and seeding of implantable medical devices. Patients with S aureus bacteremia commonly present with fever or symptoms from metastatic infection, such as pain in the back, joints, abdomen or extremities, and/or change in mental status. Risk factors include intravascular devices such as implantable cardiac devices and dialysis vascular catheters, recent surgical procedures, injection drug use, diabetes, and previous S aureus infection. Staphylococcus aureus bacteremia is detected with blood cultures. Prolonged S aureus bacteremia (≥48 hours) is associated with a 90-day mortality risk of 39%. All patients with S aureus bacteremia should undergo transthoracic echocardiography; transesophageal echocardiography should be performed in patients at high risk for endocarditis, such as those with persistent bacteremia, persistent fever, metastatic infection foci, or implantable cardiac devices. Other imaging modalities, such as computed tomography or magnetic resonance imaging, should be performed based on symptoms and localizing signs of metastatic infection. Staphylococcus aureus is categorized as methicillin-susceptible (MSSA) or methicillin-resistant (MRSA) based on susceptibility to β-lactam antibiotics. Initial treatment for S aureus bacteremia typically includes antibiotics active against MRSA such as vancomycin or daptomycin. Once antibiotic susceptibility results are available, antibiotics should be adjusted. Cefazolin or antistaphylococcal penicillins should be used for MSSA and vancomycin, daptomycin, or ceftobiprole for MRSA. Phase 3 trials for S aureus bacteremia demonstrated noninferiority of daptomycin to standard of care (treatment success, 53/120 [44%] vs 48/115 [42%]) and noninferiority of ceftobiprole to daptomycin (treatment success, 132/189 [70%] vs 136/198 [69%]). Source control is a critical component of treating S aureus bacteremia and may include removal of infected intravascular or implanted devices, drainage of abscesses, and surgical debridement.

Conclusions and relevance: Staphylococcus aureus bacteremia has a case fatality rate of 15% to 30% and causes 300 000 deaths per year worldwide. Empirical antibiotic treatment should include vancomycin or daptomycin, which are active against MRSA. Once S aureus susceptibilities are known, MSSA should be treated with cefazolin or an antistaphylococcal penicillin. Additional clinical management consists of identifying sites of metastatic infection and pursuing source control for identified foci of infection.

Figure 1. Pathogenicity and host interactions of Staphylococcus aureus

1) Immune evasion. A. Neutrophils. i) Neutrophil chemotaxis and activation are inhibited by Staphylococcal superantigen-like proteins, chemotaxis-inhibitory protein of Staphylococcus (CHIPS), and staphopain. ii) Neutrophils are destroyed by pore-forming toxins – bicomponent leukocidins (Panton–Valentine leukocidin [PVL], γ-haemolysin AB and γ-haemolysin CB, leukocidin ED, leukocidin AB) and phenol-soluble modulins. iii) Survival within neutrophils – inhibition of oxidative stress mechanisms through expression of the golden pigment staphyloxanthin, inhibition of myeloperoxidase (MPO) by the staphylococcal peroxidase inhibitor (SPIN), and the antioxidants superoxide dismutase A (SodA), SodM, catalase KatG, and alkylhydroperoxide reductase (AhpC). Positively charged antimicrobial peptides are countered by reducing the negative charge of the cell wall and by proteolysis of the antimicrobial peptides. B. Antibody responses. i) Staphylococcal surface protein A (SpA) binds the Fc region of IgG, to hamper phagocytosis. ii) Cross-links B cell IgM receptors, resulting in B cell apoptosis. C. Complement. Numerous factors which inhibit complement mediated opsonisation. Particularly targeted are C3 related pathways with proteins such as staphylococcal complement inhibitor (SCIN) inhibiting the key enzyme C3 convertase and Ecb, Efb and Eap interacting with other aspects of the C3 convertase complex (C3d, C3b, C4b). 2) Abscesses. Seeding to tissues with establishment of micro-colonies of S. aureus and accumulation of neutrophils. Replication requires iron acquisition via IsdA, B, C proteins, and avoidance of neutrophil killing. Coagulase (Coa) and von Willebrand factor binding protein (vWbp) promote fibrin clots and a pseudocapsule, protecting the central bacterial aggregate from phagocytic clearance. 3) Biofilm. Initial attachment to surfaces is via fibronectin-binding proteins FnBPA and FnBPB, clumping factor A (ClfA) and clumping factor B (ClfB), serine-aspartate repeat family proteins (SdrC, SdrD, and SdrE), and bone sialoprotein-binding protein (Bbp). Microcolonies of S. aureus then produce an extracellular polymeric substance made of polysaccharides (such as polysaccharide intercellular adhesin [PIA]), proteins and extracellular DNA. PIA production is dependent on the ica operon. FnBPA, FnBPB, and SdrC also promote cell-cell interactions leading to increased biofilm formation. Biofilm dispersal is mediated by proteases from several families (serine proteases, cysteine proteases, metalloprotease), nucleases (Nuc1 and Nuc2), and phenol-soluble modulins. Biofilm formation is tightly regulated via quorum-sensing systems (e.g., Agr system). Further description of figure: Picture of S. aureus in the bloodstream with illustration of the following text: Immune Evasion: 1) Neutrophils a. Neutrophil chemotaxis and activation are inhibited by Staphylococcal superantigen-like proteins, chemotaxis-inhibitory protein of Staphylococcus (CHIPS), and staphopain. b. Neutrophils are destroyed by pore-forming toxins – bicomponent leukocidins (Panton–Valentine leukocidin [PVL], γ-haemolysin AB and γ-haemolysin CB, leukocidin ED, leukocidin AB) and phenol-soluble modulins. c. Survival within neutrophils – inhibition of oxidative stress mechanisms through expression of the golden pigment staphyloxanthin, inhibition of myeloperoxidase (MPO) by the staphylococcal peroxidase inhibitor (SPIN), and the antioxidants superoxide dismutase A (SodA), SodM, catalase KatG, and alkylhydroperoxide reductase (AhpC). Positively charged antimicrobial peptides are countered by reducing the negative charge of the cell wall and by proteolysis of the antimicrobial peptides. 2) Antibody responses a. Staphylococcal surface protein A (SpA) binds the Fc region of IgG, to hamper phagocytosis b. Cross-links B cell IgM receptors, resulting in B cell apoptosis 3) Complement a) Numerous factors which inhibit complement mediated opsonisation. Particularly targeted are C3 related pathways with proteins such as staphylococcal complement inhibitor (SCIN) inhibiting the key enzyme C3 convertase and Ecb, Efb and Eap interacting with other aspects of the C3 convertase complex (C3d, C3b, C4b). Following evasion of host responses in the bloodstream arrows to and from: 1) Abscesses; 2) Biofilms. Picture of abscess. Text: Seeding to tissues with establishment of micro-colonies of S. aureus and accumulation of neutrophils. Replication requires iron acquisition via IsdA, B, C proteins, and avoidance of neutrophil killing. Coagulase (Coa) and von Willebrand factor binding protein (vWbp) promote fibrin clots and a pseudocapsule, protecting the central bacterial aggregate from phagocytic clearance. Picture of biofilm forming on device. Text: Initial attachment to surfaces is via fibronectin-binding proteins FnBPA and FnBPB, clumping factor A (ClfA) and clumping factor B (ClfB), serine-aspartate repeat family proteins (SdrC, SdrD, and SdrE), and bone sialoprotein-binding protein (Bbp). Microcolonies of S. aureus then produce an extracellular polymeric substance made of polysaccharides (such as polysaccharide intercellular adhesin [PIA]), proteins and extracellular DNA. PIA production is dependent on the ica operon. FnBPA, FnBPB, and SdrC also promote cell-cell interactions leading to increased biofilm formation. Biofilm dispersal is mediated by proteases from several families (serine proteases, cysteine proteases, metalloprotease), nucleases (Nuc1 and Nuc2), and phenol-soluble modulins. Biofilm formation is tightly regulated via quorum-sensing systems (e.g., Agr system). Then a column for therapeutic implications with 3 boxes and text: 1. Antibiotics – appropriate choice and duration of antibiotic therapy is required to kill S. aureus bacteria which have evaded the host immune response. 2. Identify and control source – in an abscess, antibiotic penetration is reduced and proliferating bacteria are protected from host immune killing. Abscesses may be an ongoing source of bacteremia. 3. Remove infected devices – biofilm on implanted devices protects bacteria from host immune killing and the low metabolic state of bacteria results in antibiotic tolerance. Dispersal from biofilms may be an ongoing source of bacteremia.

Figure 2. Diagnostic evaluation of patients with Staphylococcus aureus bacteremia

Note: Additional discussion is provided in the article main text regarding the respective uses of transthoracic and transesophageal echocardiography, and of CT and MRI spine imaging.