Staphylococcus aureus infection

Staphylococcus aureus infection Main page
Overview
Classification
Pathophysiology
Causes

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fatimo Biobaku M.B.B.S [2], Usama Talib, BSc, MD [3] Alberto Castro Molina, M.D.

Overview

Staphylococcus aureus is the most common cause of staph infections. It is understood that amongst the general population 20–30% carry Staphylococci irrespective of being symptomatic. Staphylococcus aureus is associated with a number of illnesses including insignificant infections of the skin, like furuncles, impetigo, folliculitis, pimples, abscesses, boils, cellulitis, carbuncles and scalded skin syndrome. It can also lead to various conditions that can be life-threatening such as endocarditis, toxic shock syndrome (TSS), meningitis, pneumonia, osteomyelitis, and septicemia. It can involve soft tissue, skin, joints, respiratory, musculoskeletal and cardiovascular systems. It is also known to cause nosocomial infections very commonly. Post surgical infections of the wound is also caused by Staphylococcus aureus.

S. aureus was discovered in 1880 by Sir Alexander Ogston, a surgeon from Aberdeen, Scotland, in pus from surgical abscesses. Moore than 500,000 patients in the US acquire a staphylococcal infection every year.

Staphylococcus aureus remains a major cause of both community-acquired and health care-associated invasive infections worldwide. In 2019, S. aureus was reported as the leading bacterial cause of death in 135 countries. Among multidrug-resistant bacterial infections in hospitalized patients in the United States in 2017, an estimated 52% were caused by methicillin-resistant S. aureus (MRSA).

S. aureus bacteremia is one of the most clinically important manifestations of infection because of its propensity to seed metastatic foci, including infective endocarditis, vertebral osteomyelitis, septic arthritis, epidural abscess, and deep-seated device-associated infection. Despite improvements in diagnosis and treatment, the 90 day mortality among patients with S. aureus bacteremia remains high, approximately 27%. Contemporary management emphasizes early recognition, prompt administration of appropriate antibiotics, repeat blood cultures, evaluation for endocarditis and metastatic infection, and aggressive source control.

Classification

Staphylococcal infections can be classified according to the various organ systems involved. Staphylococcal infections may encompass skin and soft tissue, respiratory system, parroted glands, gastrointestinal system, eyes, musculoskeletal system, blood and cardiovascular system, central nervous system and urinary system.

Organ System Diseases Skin Skin abscess Impetigo Boils Carbuncles Furuncle Cellulitis Folliculitis Scalded skin syndrome Pimples Wound infection Respiratory Pneumonia Sinusitis Pulmonary abscess Parotid Parotitis GIT Peritonitis Food poisoning Eye Soft tissue infection Musculoskeletal Osteomyeitis Pyomyositis Septic arthritis Infection of replaced joint Deep tissue infection CVS & blood Infectious endocarditis Bacteremia Sepsis Toxic shock syndrome Thrombophlebitis CVS Meningitis Urogential Urinary tract infections

Staphylococcus aureus infections may also be classified according to microbiologic susceptibility and clinical syndrome:

• By antimicrobial susceptibility
  • Methicillin-susceptible Staphylococcus aureus (MSSA)
  • Methicillin-resistant Staphylococcus aureus (MRSA)
• By clinical course in bacteremia
  • Uncomplicated S. aureus bacteremia
  • Complicated S. aureus bacteremia
• By pathobiology
  • Colonization
  • Toxin-mediated disease
  • Localized invasive infection
  • Hematogenous or metastatic invasive infection

Pathophysiology

Staphylococcus aureus is a highly virulent bacteria that has been recognized as a cause of a wide variety of diseases in humans. Approximately 60% of humans are colonized with Staphylococcus aureus (the nasal membranes and skin are the common habitat). Several strains of Staphylococcus aureus bacteria exist. The characteristic attribute of a particular strain such as toxins and extracellular factors, invasive properties (such as adherence, biofilm formation, and resistance to phagocytosis), as well as the immune defense mechanisms of the host, majorly determine the pathogenesis of Staphylococcus aureus infection. Staphylococcus aureus causes several infections ranging from mild infections to invasive diseases that are life threatening. Infections caused by Staphylococcus aureus include skin and soft tissue infections, osteomyelitis, food poisoning, pneumonia, infective endocarditis and sepsis. Some of the virulence factors that have been recognized in the pathogenesis of Staphylococcus aureus infections include:

• Staphylococcal superantigens

1. These have been strongly implicated in a wide range of illnesses such as toxic shock syndrome and staphylococcal food poisoning.
2. Several studies also suggest staphylococcal superantigens play a role in diseases such as atopic dermatitis, some forms of psoriasis, Kawasaki disease, and chronic rhinosinusitis.
3. Staphylococcal superantigens are exotoxins with more than 20 distinct types, and most staphylococcus aureus strains encode many superantigen gene. Staphylococcus superantigens include staphylococcal enterotoxins, staphylococcal enterotoxin-like proteins, and toxic shock syndrome toxin-1.
4. Staphylococcal enterotoxins cause food poisoning via ingestion of contaminated food. These enterotoxins have a very high stability and they are not easily denatured by heat and low pH (mild cooking or food digestion in the stomach cannot easily eradicate these toxins).
5. Unlike most conventional peptides that stimulate roughly 1% of naive T-cells, a staphylococcal superantigen can simultaneously activate a large proportion of T lymphocytes (up to 20%).
6. Staphylococcal superantigens are distinct because of their ability to bypass highly specific antigen-driven interaction between T-cells and antigen presenting cells.
7. The superantigens can uniquely activate T lymphocytes by directly crosslinking certain TCR Vβ (T cell receptor β-chain variable domain).
8. Numerous superantigen-activated T cells can then release several proinflammatory cytokines (this can lead to a “cytokine storm” phenomenon in severe cases, as seen in toxic shock syndrome). Superantigens also activate antigen presenting cells and this contributes to cytokine release.

• Alpha-hemolysin (α-toxin)

1. This has been implicated in skin and soft tissue infections, and invasive Staphylococcus aureus diseases.
2. It is a pore-forming cytotoxin, it forms transmembrane pores on the surface of target cells.
3. Imbalance in ion homeostasis occur as a result of the pore formation (efflux of potassium cations and ATP or influx of calcium ions). This eventually result in cell death. Alpha-toxin targets a variety of cell types including epithelial and endothelial cells, platelets and blood cells.
4. Alpha-hemolysin activates alpha-hemolysin receptor (a disintegrin and metalloprotease 10), contributing to proteolysis of E-cadherin. This results in the disruption of the adherens junction in the epithelial layer. Remodeling of the epithelial layer occurs and pathogen dissemination ensues.
5. Proteolysis of the extracellular domain of vascular endothelial cadherin can also occur, contributing to the breach of blood vessel endothelium integrity.
6. Alpha-toxin has been shown to promote strong host inflammatory responses which has been linked to increased morbidity and mortality.
7. Alpha-toxin can activate intracellular host sensor molecules such as nucleotide-binding domain leucine-rich repeat containing (NLR) family (NLRC2 and NLRP3).
8. The activation of the NLRP3 inflammasome by alpha-toxin and costimulation of NLRC2 by alpha-toxin and muramyl dipeptide, trigger the activation of caspase 1. This subsequently result in the activation of proinflammatory cytokine IL-1β which majorly contributes to the influx of polymorphonuclear leukocytes to the site of infection.
9. Sizes of abscesses have been shown to significantly reduce following functional inactivation of the gene encoding alpha-hemolysin.

• Bicomponent leukocidins

1. These include Panton-Valentine leukocidin (LukF-PV and LukS-PV), γ-hemolysins (HlgAB and HlgCB), LukED, and LukAB.
2. Similar to the alpha-toxin, leukocidins are also Staphylococcus aureus pore-forming toxins.
3. More than one leukocidin is often encoded by a S. aureus strain, and different leukocidins can target the same cell types and receptors.
4. Leukocidins have been associated with staphylococcal skin and soft tissue infections, bacteremia, severe pneumonia.

• Biofilm formation

1. S. aureus can adhere to prosthetic material and form biofilms on intravascular catheters, prosthetic valves, cardiac implantable electronic devices, and orthopedic implants.
2. Biofilm formation contributes to persistence of infection, difficulty achieving microbiologic cure, and the need for device removal or surgical source control.

Epidemiology and Demographics

The incidence of S. aureus bacteremia ranges from approximately 9.3 to 65 cases per 100,000 person-years in high-income countries. S. aureus infection affects all age groups but is more common in persons at the extremes of age, especially infants younger than 1 year and adults older than 70 years. Men are affected more frequently than women, with an approximate male to female ratio of 1.5:1.

The epidemiology of invasive S. aureus infection has changed over time. Although the proportion of cases complicated by infective endocarditis has decreased compared with historical cohorts, infections associated with prosthetic material and intravascular devices have increased substantially. In a 21 year prospective study, more than half of patients with S. aureus bacteremia had implanted prosthetic material.

Risk Factors

Risk factors for invasive Staphylococcus aureus infection and S. aureus bacteremia include:

• Central venous catheters
• Implantable cardiac or other prosthetic devices
• Injection drug use
• Hemodialysis, especially when vascular access is via central venous catheter
• Recent surgical procedures
• Male sex
• Very young age or older age
• Lower socioeconomic status
• Diabetes mellitus
• Corticosteroid use
• HIV infection
• Nasal colonization with S. aureus

Persons who inject drugs are at particularly high risk of invasive MRSA infection.

Diagnosis

History and Symptoms

The clinical presentation of Staphylococcus aureus infection varies depending on the site of infection. Patients may present with localized skin and soft tissue symptoms, fever, hypotension, dyspnea, focal pain, back pain, joint pain, or signs of metastatic infection. In patients with S. aureus bacteremia, clinicians should specifically evaluate for symptoms suggesting metastatic seeding, including endocarditis, vertebral osteomyelitis, epidural abscess, septic arthritis, and deep tissue abscess.

Physical Examination

A careful physical examination should be performed to identify the primary focus of infection and any evidence of metastatic infection. Important findings may include:

• Skin and soft tissue abscess
• Cardiac murmur suggestive of infective endocarditis
• Spine tenderness
• Joint swelling or tenderness
• Signs of infected prosthetic material
• Peripheral stigmata of endocarditis
• Hemodynamic instability in severe infection or sepsis

Laboratory Findings

Essential laboratory evaluation in suspected invasive S. aureus infection includes:

• Blood cultures
• Complete blood count
• Renal function tests
• Liver function tests
• Inflammatory markers
• Repeated blood cultures in patients with documented S. aureus bacteremia to establish clearance of bacteremia

Methicillin susceptibility testing should be performed to classify isolates as MSSA or MRSA, since definitive antibiotic therapy depends on susceptibility results.

Echocardiography

Echocardiography is often indicated in S. aureus bacteremia because of the risk of infective endocarditis. Transesophageal echocardiography is generally preferred in patients with prosthetic valves, cardiac devices, prolonged bacteremia, clinical suspicion for endocarditis, or other high-risk features.

CT scan and MRI

Other imaging modalities, such as CT or MRI, should be performed based on symptoms and localizing signs of metastatic infection. Examples include:

• MRI of the spine for suspected vertebral osteomyelitis or epidural abscess
• CT of the chest for suspected pulmonary septic emboli or pneumonia
• Cross-sectional imaging of symptomatic areas to identify abscesses or deep-seated infection

Other Diagnostic Studies

Additional diagnostic management consists of:

• Identifying sites of metastatic infection
• Pursuing source control for identified foci of infection
• Assessing for infected prosthetic material
• Repeating blood cultures until microbiologic clearance is documented

Treatment

Medical Therapy

The management of invasive Staphylococcus aureus infection depends on the infection syndrome, antimicrobial susceptibility pattern, and the presence or absence of deep-seated or metastatic infection. In patients with suspected S. aureus bacteremia, empiric treatment should generally include antibiotics active against MRSA, such as:

• Vancomycin
• Daptomycin

Once susceptibility results are available, therapy should be adjusted:

• For MSSA
  • Cefazolin
  • Antistaphylococcal penicillins such as nafcillin or oxacillin
• For MRSA
  • Vancomycin
  • Daptomycin
  • Ceftobiprole

The treatment success of daptomycin has been shown to be noninferior to standard therapy in S. aureus bacteremia. In more recent data, ceftobiprole was noninferior to daptomycin for complicated S. aureus bacteremia.

For uncomplicated S. aureus bacteremia, a minimum of 14 days of intravenous therapy is generally recommended after clearance of blood cultures and exclusion of endocarditis or metastatic infection. Complicated bacteremia, endocarditis, osteomyelitis, prosthetic infection, or deep-seated abscesses typically require longer treatment courses, often 4 to 6 weeks or more depending on the site and extent of infection.

Source Control

Source control is a critical component of treatment and may include:

• Removal of infected intravascular catheters
• Removal of infected implanted devices when feasible
• Drainage of abscesses
• Surgical debridement of infected tissue
• Evaluation and management of metastatic infection foci

Surgery

Surgical management may be indicated in selected patients with:

• Infective endocarditis with valvular destruction or uncontrolled infection
• Deep tissue abscess requiring drainage
• Prosthetic joint infection
• Osteomyelitis requiring debridement
• Device-related infection requiring explantation

Prevention

Prevention strategies include:

• Adherence to infection control practices in hospitals
• Proper catheter care and limiting unnecessary intravascular device use
• Perioperative infection prevention measures
• Prompt recognition and treatment of skin and soft tissue infection
• In selected settings, decolonization strategies for carriers of S. aureus may reduce infection risk