Staphylococcus aureus bacteremia in children: Epidemiology and clinical features

INTRODUCTION — Staphylococcus aureus is a leading cause of both community- and healthcare-associated bacteremia. S. aureus bacteremia (SAB) is associated with increased morbidity and mortality, even with appropriate therapy.

The epidemiology and clinical features of SAB in children will be reviewed here. The management and outcome of SAB in children are discussed separately. (See "Staphylococcus aureus bacteremia in children: Management and outcome".)

This topic focuses specifically on bacteremia. Other issues related to S. aureus infections are discussed separately:

●(See "Staphylococcus aureus in children: Overview of treatment of invasive infections".)

●(See "Methicillin-resistant Staphylococcus aureus infections in children: Epidemiology and clinical spectrum".)

●(See "Methicillin-resistant Staphylococcus aureus (MRSA) in children: Prevention and control".)

●(See "Methicillin-resistant Staphylococcus aureus (MRSA): Microbiology".)

EPIDEMIOLOGY

Incidence — The overall incidence of pediatric SAB varies somewhat by region, ranging from 4 to 20 per 100,000 [1-5]. The incidence of SAB in children increased throughout the early 2000s to 2010s [3,6-9]. In one study, the increase was attributed largely to methicillin-resistant S. aureus (MRSA) bacteremia [7]. The rate of SAB among hospitalized children ranges from 1.5 to 3.5 per 1000 hospital admissions [7,9,10].

Using a large database representing 20 percent of pediatric hospitalizations in the United States, the incidence of non-neonatal methicillin-susceptible S. aureus (MSSA) bloodstream infections (BSIs) increased from 0.83 per 1000 admissions in 2009 to 1.98 per 1000 admissions in 2016 [11]. The study did not detect significant changes in the incidence of MRSA BSIs during the same time period. In this study, MSSA and MRSA accounted for a sizable proportion of all BSIs occurring outside of the neonatal age range (14 and 9 percent, respectively).

Rates of invasive S. aureus infections do not appear to have been significantly impacted by the coronavirus disease 2019 (COVID-19) pandemic and related social distancing, masking, and other infection mitigation practices. In a report from one children's hospital in the United States, rates of invasive S. aureus infections before and after 2020 remained stable despite considerable decreases in other bacterial infections, particularly invasive streptococcal infections (eg, pneumococcus and group A streptococcus) [12]. However, streptococcal infections subsequently rose sharply as pandemic restrictions were lifted, as discussed separately. (See "Invasive group A streptococcal infections in children", section on 'Incidence'.)

Infection source — Most cases of SAB in children are associated with a localized infection source (eg, bone and joint infections, skin and soft tissue infections, pneumonia) or invasive device (eg, central venous catheter). SAB without a focus of infection accounts for <10 percent of SAB episodes, most of which occur in children with comorbidities [13,14].

The source of SAB differs depending on whether the infection is community- or healthcare-associated, as discussed in the following sections.

Community-associated SAB — Community-associated infections are those that occur in patients without risk factors for healthcare-associated infection (eg, no invasive devices or recent hospitalizations) with onset in the community (ie, in a nonhospitalized patient or within first 48 hours of a hospital admission).

Approximately 40 to 50 percent of SAB episodes are community-associated [1,2,8,15-17].

In otherwise healthy children, community-associated SAB is frequently related to a focus of infection, including [2,18,19]:

●Bone and joint infections. (See "Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology", section on 'Microbiology' and "Bacterial arthritis: Epidemiology, pathogenesis, and microbiology in infants and children", section on 'Microbiology'.)

●Skin and soft tissue infections. (See "Cellulitis and skin abscess: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Microbiology' and "Skin and soft tissue infections in children >28 days: Evaluation and management".)

●Pneumonia – In particular, SAB may occur in children with influenza who develop a secondary S. aureus pneumonia [20]. (See "Pneumonia in children: Epidemiology, pathogenesis, and etiology", section on 'Etiologic agents' and "Seasonal influenza in children: Clinical features and diagnosis", section on 'Complications'.)

●Infective endocarditis (IE) – IE is an uncommon source of SAB in childhood. Nevertheless, S. aureus remains the predominant causative organism of pediatric IE causing infective endocarditis in children. (See "Infective endocarditis in children", section on 'Microbiology'.)

Community-associated MRSA (CA-MRSA) infection is discussed separately. (See "Methicillin-resistant Staphylococcus aureus infections in children: Epidemiology and clinical spectrum", section on 'CA-MRSA infection'.)

Healthcare-associated SAB — This category refers to infections that are acquired in a healthcare setting or that are associated with any of the following:

●Invasive devices

●History of surgery, hospitalization, or dialysis within the past year

●Prior history of healthcare-associated S. aureus infection or colonization

Approximately 50 to 60 percent of SAB episodes in children are healthcare-associated [1,2,8,15-17].

Healthcare-associated infections are further classified based upon whether onset is in the community or hospital.

Community onset — This category refers to infection in a patient with one or more of the above risk factors for healthcare-associated infection with onset in the community (ie, in a nonhospitalized patient or within first 48 hours of a hospital admission). Approximately one-third to one-half healthcare-associated SAB episodes are community onset [1,2].

Community-onset healthcare-associated SAB typically affects children with chronic illnesses (eg, cancer, neurologic disorders, gastrointestinal disorders requiring home parenteral nutrition) [16]. The rate of community-onset healthcare-associated SAB has risen with increasing use of outpatient intravenous therapies [16,21-24]. (See 'Intravascular catheters' below.)

In one large multicenter study from Australia and New Zealand, the source of bacteremia among children with community-onset healthcare-associated SAB was as follows [2]:

●Central venous catheter (CVC) or other device infection (26 percent)

●Skin or soft tissue infection (21 percent)

●Bone and joint infection (14 percent)

●No identified source (19 percent)

Hospital onset — Hospital-onset (or nosocomial) healthcare-associated infections are those that occur >48 hours after hospital admission. One-half to two-thirds of healthcare-associated SAB episodes are hospital onset [1,2,25].

SAB is a leading cause of nosocomial BSIs in children, particularly among children with CVCs [6,26-29]. Preterm neonates are at particularly high risk of nosocomial SAB, which most commonly occurs in association with an indwelling CVC [16,25,30,31].

Other risk factors for nosocomial SAB in children are similar to those described in adults and relate mainly to intravascular devices, respiratory illness, and surgical wounds [16,24,32,33]. (See "Epidemiology of Staphylococcus aureus bacteremia in adults", section on 'Risk factors'.)

Nosocomial SAB is a serious infection with mortality ranging from 4 to 9 percent in children [2,10,30]. Nosocomial SAB also may be associated with metastatic complications, including septic pulmonary emboli and, rarely, infective endocarditis. (See "Staphylococcus aureus bacteremia in children: Management and outcome", section on 'Outcome' and "Infective endocarditis in children".)

ANTIMICROBIAL RESISTANCE

Methicillin resistance — Methicillin-resistant S. aureus (MRSA) was initially a healthcare-associated pathogen, with only small numbers of community-acquired cases, but it has become a prevalent community-acquired pathogen.

The epidemiology, microbiologic characteristics, and risk factors for methicillin resistance are discussed in detail separately. (See "Methicillin-resistant Staphylococcus aureus infections in children: Epidemiology and clinical spectrum".)

Clindamycin resistance — Resistance to clindamycin may be constitutive or inducible via the macrolide-lincosamide-streptogramin B (MLS[B]) resistance mechanism. Isolates with constitutive clindamycin resistance are fully resistant to both erythromycin and clindamycin and can be detected with routine susceptibility testing. MRSA isolates with inducible resistance via the MLS(B) mechanism can develop resistance during therapy; these isolates appear susceptible to clindamycin and resistant to erythromycin by most standard techniques but can be detected using the "D test" (picture 1). Automated systems are available that can screen for inducible resistance to clindamycin, with results comparable with the standard D test [34]. (See "Overview of antibacterial susceptibility testing", section on 'Inducible clindamycin resistance testing'.)

Clindamycin resistance in community-associated S. aureus can have considerable regional and temporal variation. The proportion of MRSA isolates that are resistant to clindamycin has increased since the early 2000s [35]. Clinicians must remain vigilant for increasing clindamycin resistance among community-associated MRSA, especially since clindamycin is commonly used to treat these infections in children [36,37]. We suggest not using clindamycin to complete therapy for selective invasive infections associated with SAB until or unless the isolate is known to be susceptible to this agent and blood cultures are negative [38,39]. (See "Staphylococcus aureus bacteremia in children: Management and outcome", section on 'Definitive therapy'.)

Vancomycin resistance — S. aureus isolates with intermediate susceptibility or resistance to vancomycin are much less common than MRSA. Bacteremia has been described [40]. These infections are discussed elsewhere. (See "Staphylococcus aureus bacteremia with reduced susceptibility to vancomycin".)

Reduced susceptibility to ceftaroline — Although ceftaroline is not widely used in the treatment of MRSA bacteremia in children, in one report, reduced susceptibility to ceftaroline (minimum inhibitory concentration ≥2 mcg/mL) was found in almost 3 percent of 201 invasive MRSA isolates from children between the years 2015 to 2018. All isolates with reduced susceptibility were from children with healthcare-associated infections; none had received ceftaroline prior to the recovery of the MRSA isolate [41,42].

RISK FACTORS — The following clinical conditions predispose patients to develop SAB:

●Intravascular catheters

●Indwelling foreign body or prosthesis

●Underlying medical conditions (eg, malignancy, end-stage kidney disease [ie, dialysis dependent], eczema and other dermatologic conditions)

●Nasal S. aureus colonization

●Injection drug use

Intravascular catheters — Intravascular catheters serve as a direct conduit into the intravascular space, allowing easy access for pathogens such as S. aureus into the bloodstream.

Intravascular catheters are the most common predisposing cause for SAB in hospitalized patients and an increasingly important contributor to community-onset healthcare-associated infections [16,21-23,26,29,32,43].

In a report from the National Nosocomial Infections Surveillance System, >90 percent of episodes of nosocomial bacteremia detected in patients in the pediatric intensive care unit setting were associated with central venous catheters [26]. In 144 pediatric intensive care units reporting data to the Centers for Disease Control and Prevention from 1997 through 2007, methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) accounted for 2.6 and 5.3 percent of all catheter-associated bloodstream infections (BSIs), respectively [44].Catheter-associated infections account for approximately one-third of pediatric SAB episodes overall and up to three-quarters of nosocomial episodes [14,16,29].

The risk of bacteremia varies depending on the type of catheter (eg, peripherally inserted versus centrally inserted, tunneled versus nontunneled), insertion site (upper versus lower extremity, internal jugular versus femoral vein), and duration of catheterization. These issues are discussed in greater detail separately. (See "Intravascular catheter-related infection: Epidemiology, pathogenesis, and microbiology".)

Implanted foreign body — Any implanted foreign body that becomes infected is a potential source for SAB. Implanted devices include vascular, urologic, neurologic, and orthopedic prostheses and devices. In a report of 47 episodes of implant-associated S. aureus infection in pediatric patients, three cases (7 percent) had associated bacteremia; all three were associated with spinal instrumentation [45].

Underlying medical conditions — Underlying medical conditions are associated with an increased risk of SAB in children. In a retrospective review of 164 episodes of SAB in 151 children, 74 percent of patients had an underlying medical condition, including heart disease (24 percent), malignancy (18 percent), premature birth (12 percent), gastrointestinal disorder (7 percent), transplant recipient (7 percent), and end-stage kidney disease (5 percent) [16]. Approximately one-half of cases had onset in hospital. In one study of 232 children with MRSA bacteremia, 52 percent had a comorbid condition [19].

Hemodialysis-dependent and diabetic patients have high rates of nasal and skin colonization with S. aureus [46-48]. Such patients are more prone to S. aureus infection [46,48], including SAB [46,49]. (See "Tunneled hemodialysis catheter-related bloodstream infection (CRBSI): Management and prevention".)

Rare inherited defects in white blood cell function or immune responses can also predispose patients to recurrent staphylococcal infections [50]. These include:

●Hyperimmunoglobulin E recurrent infection syndrome (HIES; previously called Job syndrome) (see "Autosomal dominant hyperimmunoglobulin E syndrome")

●Chronic granulomatous disease (see "Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis")

●Leukocyte adhesion deficiency(see "Leukocyte-adhesion deficiency")

●Chediak-Higashi syndrome (see "Chediak-Higashi syndrome")

●Wiskott-Aldrich syndrome (see "Wiskott-Aldrich syndrome")

Nasal colonization — The role of nasal colonization in the development of SAB was prospectively evaluated in a study in which more than 14,000 nonbacteremic, nonsurgical adults were screened for nasal S. aureus carriage on hospital admission [51]. Nosocomial SAB occurred significantly more often in the 24 percent of patients who were nasal carriers (1.2 versus 0.4 percent in noncarriers). Genotyping demonstrated that 80 percent of strains causing SAB in nasal carriers were endogenous. On the other hand, nasal carriers had significantly lower rates of SAB-related mortality (3 of 40 versus 13 of 41 [8 versus 32 percent]), a difference that could not be explained by differences in age or comorbidities.

Differences in the immune response of S. aureus carriers and noncarriers may help to explain the lower mortality among carriers. Support for this hypothesis comes from an observational study in which nasal swabs and serum samples were obtained from healthy blood donors [52]. Carriers of S. aureus demonstrated effective antibody response against the colonizing strain, whereas the antibody response against other strains was similar to that of noncarriers. This strain-specific immunity may contribute to the improved mortality outcome for nasal carriers compared with noncarriers. How these findings relate to children is unknown.

A more marked increase in the risk of infection has been described in patients who are colonized with MRSA at hospital admission. What role nasal carriage of S. aureus plays in the pathogenesis of SAB with onset in the community as opposed to the hospital is not clear. (See "Methicillin-resistant Staphylococcus aureus infections in children: Epidemiology and clinical spectrum", section on 'Colonized individuals'.)

Injection drug use — The role of injection drug use in SAB is discussed separately. (See "Epidemiology of Staphylococcus aureus bacteremia in adults", section on 'Injection drug use'.)

CLINICAL FEATURES — SAB frequently occurs in association with fever and other symptoms related to the source of infection.

Sepsis — Septic shock is characterized by signs of inadequate tissue perfusion with evidence of systemic inflammation (ie, abnormal temperature, white blood cell count, heart rate, and/or respiratory rate). (See "Septic shock in children in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)" and "Sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis".)

Toxic shock syndrome — Toxic shock syndrome (TSS) can be due to streptococcal or staphylococcal infections. Bacteremia is common in the former but rare in staphylococcal TSS. Manifestations of TSS include fever, hypotension, and erythroderma (picture 2). (See "Staphylococcal toxic shock syndrome".)

Osteomyelitis — Children with hematogenous osteomyelitis usually present acutely with fever, constitutional symptoms (eg, irritability, decreased appetite or activity), focal findings of bone inflammation (warmth, swelling, point tenderness), and limitation of function (eg, limp, limited use of extremity). (See "Hematogenous osteomyelitis in children: Clinical features and complications".)

Septic arthritis — Bacterial arthritis classically presents with acute onset (two to five days) of fever and joint pain, swelling, and limited range of motion. However, the presentation varies depending upon the age of the child and the site of infection. Osteomyelitis contiguous to the septic arthritis is common. (See "Bacterial arthritis: Clinical features and diagnosis in infants and children", section on 'Clinical features'.)

Pneumonia — SAB may be associated with pneumonia, with typical symptoms of fever, cough, and tachypnea. Complications such as necrotizing pneumonia, parapneumonic effusion, empyema, and lung abscess are frequently associated with S. aureus pneumonia. (See "Community-acquired pneumonia in children: Clinical features and diagnosis" and "Epidemiology, clinical presentation, and evaluation of parapneumonic effusion and empyema in children".)

Skin and soft tissue infections — Skin and soft tissue infections in children, particularly infections that are purulent/fluctuant, are commonly caused by S. aureus. Bacteremia is uncommon in uncomplicated skin and soft tissue infections but may occur in certain settings (eg, surgical wound infections, burns, patients with underlying risk factors). (See "Skin and soft tissue infections in children >28 days: Evaluation and management".)

Intravascular catheter infection — Patients with indwelling intravascular catheters are at risk for developing SAB. Clinical manifestations may include fever, inflammation or purulence at the insertion site, hemodynamic instability, and/or catheter dysfunction. (See "Intravascular catheter-related infection: Epidemiology, pathogenesis, and microbiology" and "Intravascular non-hemodialysis catheter-related infection: Clinical manifestations and diagnosis".)

Infective endocarditis — Infective endocarditis, especially in community-acquired SAB, is much less frequent in children than in adults (1.4 percent in children compared with up to 30 percent in adults) [15]. The risk is higher in children with congenital heart disease and/or indwelling central venous catheters [53]. Clinical symptoms of infective endocarditis include a new or changing murmur and/or septic emboli. (See "Infective endocarditis in children".)

SUMMARY

●Epidemiology – Staphylococcus aureus is an important cause of both community- and healthcare-associated bacteremia. Most episodes of S. aureus bacteremia (SAB) in children are associated with a localized infection source (eg, bone and joint infections, pneumonia, skin and soft tissue infections) or invasive device (eg, central venous catheter). (See 'Epidemiology' above.)

●Antibiotic resistance – Methicillin-resistant S. aureus (MRSA) has become a prevalent community-acquired pathogen. S. aureus isolates have also developed resistance to clindamycin and, in rare cases, vancomycin. (See 'Antimicrobial resistance' above and "Methicillin-resistant Staphylococcus aureus infections in children: Epidemiology and clinical spectrum".)

●Risk factors – Important risk factors for SAB include (see 'Risk factors' above):

•Intravascular catheters

•Indwelling foreign body or prosthesis

•Underlying medical conditions

•Nasal S. aureus colonization

•Injection drug use

●Clinical features – The clinical features of SAB are largely related to the source of infection. (See 'Clinical features' above.)