Staphylococcus aureus bacteremia in children: Management and outcome

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

The treatment and outcome of SAB in children are reviewed here. The epidemiology and clinical manifestations of S. aureus bacteremia in children are discussed separately. (See "Staphylococcus aureus bacteremia in children: Epidemiology and clinical features".)

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".)

MANAGEMENT

Supportive care — Supportive measures for children with SAB may include:

●Fever management

●Respiratory support for patients with pneumonia or respiratory distress (see "Pneumonia in children: Inpatient treatment", section on 'Respiratory support' and "Acute respiratory distress in children: Emergency evaluation and initial stabilization", section on 'Initial stabilization')

●Fluid management for patients who cannot maintain adequate fluid intake (see "Maintenance intravenous fluid therapy in children")

●Volume resuscitation and/or vasopressor support for severely ill patients with signs of poor perfusion or septic shock (see "Septic shock in children in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)")

Antibiotic therapy

Empiric therapy — The choice of empiric therapy for suspected SAB in children depends on the source and severity of the infection, whether the infection is community or health care associated, and, if community associated, what the prevalence of methicillin-resistant S. aureus (MRSA) is in the community.

S. aureus isolates have developed resistance to methicillin, clindamycin, and, in rare cases, vancomycin. This is discussed in greater detail separately. (See "Staphylococcus aureus bacteremia in children: Epidemiology and clinical features", section on 'Antimicrobial resistance' and "Methicillin-resistant Staphylococcus aureus (MRSA): Microbiology".)

In most cases, SAB is suspected because there are clinical findings suggestive of a syndrome or focal infection associated with a high likelihood of SAB. Suggested empiric antimicrobial regimens in these settings are provided in separate topic reviews:

●Sepsis (see "Septic shock in children in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)", section on 'Empiric antibiotic therapy')

●Toxic shock syndrome (see "Staphylococcal toxic shock syndrome", section on 'Antibiotic therapy')

●Osteomyelitis (see "Hematogenous osteomyelitis in children: Management", section on 'Empiric parenteral therapy')

●Septic arthritis (see "Bacterial arthritis: Treatment and outcome in infants and children", section on 'Empiric parenteral therapy')

●Pneumonia/empyema (see "Pneumonia in children: Inpatient treatment", section on 'Empiric therapy' and "Management and prognosis of parapneumonic effusion and empyema in children", section on 'Antibiotic therapy')

●Skin and soft tissue infections (see "Skin and soft tissue infections in children >28 days: Evaluation and management", section on 'Management approach')

●Intravascular catheter infection

●Infective endocarditis (see "Infective endocarditis in children", section on 'Antibiotic regimens')

In children without an apparent clinical syndrome or focal source, SAB may be suspected on the basis of fever or signs of systemic infection in a child with underlying risk factors for SAB (eg, intravascular catheter or other invasive device, intravenous drug use) or on the basis of preliminary Gram stain results of cultures obtained for evaluation of fever or other nonfocal findings. In these settings, the approach to selecting empiric therapy is as follows:

●Life-threatening infection (community- or health care-associated) – For children with life-threatening infection with suspected SAB, empiric therapy consists of vancomycin plus either nafcillin or oxacillin (table 1). The combination of vancomycin plus nafcillin or oxacillin maximizes coverage for both MRSA and methicillin-susceptible S. aureus (MSSA). Gentamicin or rifampin may be added for synergy in selected circumstances (eg, severe infections associated with prosthetic devices). For patients with significant renal impairment, we typically use ceftaroline monotherapy rather than vancomycin plus oxacillin or nafcillin.

Additional antibiotics may be required for empiric treatment of non-staphylococcal pathogens until the pathogen is identified.

●Health care-associated infection – Suspected health care-associated SAB should be treated empirically with vancomycin. If the infection is life-threatening, oxacillin or nafcillin should be added, as previously discussed.

●Community-associated infection – Empiric therapy for suspected community-associated SAB depends upon the prevalence of MRSA in the community:

•Areas of low MRSA prevalence – In areas where the prevalence of community-associated MRSA is low (ie, <10 percent), empiric therapy for suspected SAB includes intravenous nafcillin, oxacillin, or cefazolin. These are the antibiotics of choice when treating bacteremia caused by MSSA. Some clinicians prefer cefazolin because of a reduced rate of phlebitis, neutropenia, and liver enzyme elevation compared with nafcillin or oxacillin.

•Areas of higher MRSA prevalence – In communities where MRSA accounts for >10 percent of the community S. aureus isolates, patients should receive an antibiotic effective against MRSA. Vancomycin is the preferred choice for empiric therapy in most cases. The approach is summarized in the table (table 1) and is discussed in greater detail separately. (See "Staphylococcus aureus in children: Overview of treatment of invasive infections", section on 'Empiric antimicrobial therapy'.)

Definitive therapy — Once susceptibilities have been determined, the antimicrobial regimen can be modified. Confirmed invasive MRSA infections are commonly treated with vancomycin; alternative regimens are summarized in the table (table 2) and are discussed in greater detail separately. (See "Staphylococcus aureus in children: Overview of treatment of invasive infections", section on 'Definitive antimicrobial therapy'.)

For SAB associated with musculoskeletal infections or pneumonia caused by clindamycin-susceptible isolates (including testing for inducible resistance), clindamycin is an appropriate choice to complete therapy once bacteremia is cleared if endovascular sites are not a concern [1]. Clindamycin is bacteriostatic for S. aureus and thus is not routinely used for the initial treatment of SAB.

Although vancomycin is generally efficacious for the treatment of MRSA, it is less effective than beta-lactams for MSSA. Thus, once results of susceptibility testing are known, S. aureus isolates that are methicillin- or penicillin-susceptible should be treated with beta-lactams rather than vancomycin (table 3).

If MRSA is not isolated within 72 to 96 hours after antibiotics are initiated, the vancomycin (or other empiric MRSA-targeting antibiotics) can be discontinued; commercial methods for rapid detection of MSSA may allow for earlier discontinuation [2]. This approach requires that clinicians be aggressive in obtaining cultures from all appropriate sites in addition to blood cultures. Aspiration or surgical incision and drainage of bone or joint infections should be performed within 48 hours of starting antibiotic treatment. (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Sites to culture' and "Bacterial arthritis: Clinical features and diagnosis in infants and children", section on 'Synovial fluid'.)

For some patients with serious infections for which S. aureus remains a potential pathogen despite negative cultures, it may be reasonable to continue therapy with an anti-MRSA antibiotic (eg, clindamycin, linezolid, or trimethoprim-sulfamethoxazole). The decision depends on the site of infection. Continued therapy despite negative cultures may be warranted for osteomyelitis, septic arthritis, and culture-negative endocarditis. This is discussed in separate topic reviews. (See "Hematogenous osteomyelitis in children: Management", section on 'Culture-negative osteomyelitis' and "Bacterial arthritis: Treatment and outcome in infants and children", section on 'Negative cultures' and "Infective endocarditis in children", section on 'Treatment'.)

Duration of therapy — The duration of therapy for SAB depends upon the source of infection:

●No source identified – Uncomplicated SAB without an identified source in otherwise healthy children >1 month old is typically treated with 10 to 14 days of parenteral antibiotics; however, the optimal duration of antibiotic therapy in this setting is not established. A shorter or longer duration of therapy may be reasonable depending of the severity of the infection. In nonsevere cases, it may be reasonable to transition to an appropriate oral antibiotic once cultures are negative and the patient has defervesced.

●Osteomyelitis or septic arthritis – SAB associated with osteomyelitis or septic arthritis is usually treated for at least three weeks. The initial treatment is with parenteral antibiotics. Most patients can be converted to an oral regimen once they have clinically improved and blood cultures are sterile. Treatment is often continued until the erythrocyte sedimentation rate is <25 to 30 mm/hour, which may take four to six weeks. This is discussed in greater detail separately. (See "Bacterial arthritis: Treatment and outcome in infants and children", section on 'Total duration' and "Hematogenous osteomyelitis in children: Management", section on 'Total duration'.)

●Skin and soft tissue infection – SAB associated with skin and soft tissue infection is usually treated for 7 to 10 days. Parenteral therapy is continued until two consecutive blood cultures are negative and the patient has clinically improved; then, treatment is completed with an oral agent based on the susceptibility of the isolate. Longer courses may be necessary depending upon clinical response. (See "Skin and soft tissue infections in children >28 days: Evaluation and management", section on 'Total duration'.)

●Catheter-related infection – Catheter-related SAB is treated with 10 to 14 days of parenteral antibiotics [3]. If the catheter is removed and bacteremia clears promptly, no further studies usually are necessary unless new clinical concerns arise. Longer duration of therapy may be warranted if bacteremia persists or if there are complications.

●Infective endocarditis – S. aureus infective endocarditis is treated parenterally for a minimum of four to six weeks, as discussed separately. (See "Infective endocarditis in children", section on 'Treatment'.)

Removal of infectious foci

Intravascular catheter removal — For children with catheter-related SAB, optimal management of the infection includes removal of the catheter [3]. However, the benefits of catheter removal must be weighed against the potential difficulty of obtaining alternative venous access. It is reasonable to attempt to clear the infection without removing the catheter in select children, particularly those who require central venous access for survival and those in whom alternative sites for catheter placement are limited [4]. Antimicrobial treatment without catheter removal is reasonable if the child is not in shock, responds promptly to medical therapy (ie, fever resolves and bacteremia clears), and has no evidence of an infected thrombus or distant sites of infection. If the catheter remains in place, both systemic antibiotics and antibiotic lock therapy may be warranted [3]. Observational studies have reported successful management in 50 to 80 percent of children treated without catheter removal [5-7]. Close monitoring is required, and the device should be removed in the event of clinical deterioration or if SAB persists for >2 days [8]. In a study of catheter-related SAB, catheter removal >4 days after infection or failure to remove the catheter, prolonged bacteremia (>4 days), and thrombocytopenia at presentation were independent predictors of complications [9]. Treatment of intravascular catheter-related infections is discussed in greater detail separately. (See "Intravascular non-hemodialysis catheter-related infection: Treatment".)

Surgical intervention — Surgical intervention may be warranted in children with infectious foci. Indications for surgical intervention are discussed separately:

●Parapneumonic effusion, empyema, or lung abscess (see "Management and prognosis of parapneumonic effusion and empyema in children", section on 'Chest tubes' and "Management and prognosis of parapneumonic effusion and empyema in children", section on 'Surgical therapy')

●Osteomyelitis (see "Hematogenous osteomyelitis in children: Management", section on 'Indications for surgery')

●Septic arthritis (see "Bacterial arthritis: Treatment and outcome in infants and children", section on 'Drainage')

●Skin abscesses (see "Skin abscesses in adults: Treatment", section on 'Incision and drainage')

Monitoring

Repeat blood cultures — Blood cultures should be repeated every 24 to 48 hours until two consecutive blood cultures are sterile [10]. Positive cultures persisting beyond 48 to 72 hours should prompt evaluations for unidentified foci of infection, such as septic thrombophlebitis, infective endocarditis, or undrained abscess.

In a retrospective study of 122 pediatric patients with SAB managed at a single institution, only one patient (0.8 percent) had a positive blood culture after two documented negative cultures (and this patient had clinical evidence of disease recurrence with new onset of septic shock on the day that the cultures reverted back to positive) [10]. Thus, documenting sterility with two consecutive blood cultures obtained at least 24 hours apart is generally sufficient.

Drug levels — For children treated with vancomycin, we generally favor trough-guided monitoring. Although area under the curve-guided dosing is suggested by consensus guidelines [11], the advantages and feasibility of this approach for most pediatric facilities remain to be determined. We aim to achieve trough concentrations of 5 to 15 mcg/mL and extend the dosing interval if the trough is ≥15 mcg/mL. Therapeutic monitoring of vancomycin in children is discussed in greater detail separately. (See "Staphylococcus aureus in children: Overview of treatment of invasive infections", section on 'Therapeutic monitoring for vancomycin'.)

Toxicity — A complete blood count should be monitored weekly for patients receiving beta-lactam antibiotics. If neutropenia occurs, it typically develops after the first 10 days of therapy. Neutropenia can also be associated with vancomycin treatment. Elevated transaminase (ie, aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) concentrations also can occur. Some authorities follow AST and ALT levels weekly, though they are rarely markedly elevated (ie, >5 times normal) and patients typically have no associated symptoms. Hypersensitivity rashes may be severe enough to require discontinuation of the beta-lactam antibiotic, although similar rashes may be encountered with clindamycin.

For patients treated with vancomycin, renal function (blood urea nitrogen and creatinine levels) should be monitored twice weekly in hospitalized patients and weekly in outpatients. More frequent monitoring may be warranted in children with renal insufficiency. However, in children with more significant renal insufficiency, it may be prudent to use an alternative agent that is not nephrotoxic, such as ceftaroline.

Echocardiography — Patients with risk factors or signs and symptoms of infectious endocarditis should undergo transthoracic echocardiography. (See "Infective endocarditis in children", section on 'Echocardiography'.)

The Infectious Diseases Society of America clinical practice guideline recommends echocardiography for children with SAB and any of the following [1]:

●Underlying congenital heart disease (CHD) or acquired valve disease

●Persistent bacteremia more than two to three days' duration

●Clinical findings suggestive of endocarditis (eg, new or changing murmur, septic emboli) (see "Infective endocarditis in children", section on 'Clinical manifestations')

Routine echocardiography is not necessary in all children with SAB. This is in contrast with the practice in adults patients, wherein routine echocardiography is recommended for all patients with SAB. (See "Clinical approach to Staphylococcus aureus bacteremia in adults", section on 'Echocardiography'.)

Infective endocarditis, especially in community-acquired SAB, occurs far less frequently in children than in adults (1.4 percent in children compared with up to 30 percent in adults) [12]. (See 'Endocarditis' below.)

OUTCOME

Mortality — The mortality of SAB in the pre-antibiotic era exceeded 80 percent [13]. In the contemporary era, mortality associated with SAB in children is approximately 2 to 3 percent [12,14-19].

In a large surveillance study from Denmark, the mortality rate associated with pediatric SAB fell from 19.6 percent in the early 1970s to 2.5 percent by the late 1990s [15].

Mortality is highest among infants <1 year of age, particularly premature neonates [14,15,20]. Other reported risk factors for mortality include comorbid conditions, hospital-acquired infection, and associated pulmonary infection or endocarditis [15,21]. In one study, the duration of time to positive blood culture was independently associated with mortality, with increased risk in patients with shorter time to positivity [22].

Rarely, patients may present with severe and rapidly progressing S. aureus sepsis, a presentation that can be fatal [23,24]. Severe sepsis can occur in previously healthy children, particularly adolescents, and may be caused by methicillin-susceptible and methicillin-resistant isolates.

Endocarditis — Patients with SAB who have underlying congenital heart disease (CHD) and those with persistent bacteremia are at increased risk of endocarditis and should undergo echocardiography. Echocardiography is also warranted if there are suggestive clinical findings (eg, new or changing murmur, septic emboli). (See 'Echocardiography' above.)

In children without CHD, infective endocarditis is a rare complication of SAB, especially in community-acquired SAB. In the largest pediatric case series, which included 140 episodes of SAB (53 percent community acquired, 47 percent nosocomially acquired), infective endocarditis occurred in 1.4 percent [12].

In a prospective series of 125 children with SAB, 19 underwent transthoracic echocardiography and none had abnormal findings [25]. In another study of 36 hospitalized children with SAB who underwent echocardiographic examination, clinically silent infective endocarditis was found in four patients, one of whom had underlying CHD [26].

In a prospective study at a tertiary care children's hospital, 51 children were identified with SAB over a three-year period [21]. Ten children developed infective endocarditis, nine of whom had underlying CHD.

In a study of catheter-related SAB in 112 children over a six-year period, endocarditis was documented in four patients, all of whom were <2 months of age; two had CHD [9].

In a study of S. aureus infections in children with CHD, 44 patients had SAB, of whom 13 (30 percent) were found to have definite infective endocarditis [27]. Prolonged bacteremia, thrombocytopenia, and elevated C-reactive protein were associated with a greater likelihood of infective endocarditis.

Management of endocarditis is discussed separately. (See "Infective endocarditis in children".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword[s] of interest.)

●Basics topic (see "Patient education: Sepsis in adults (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Supportive care – Supportive measures for children with Staphylococcus aureus bacteremia (SAB) may include fever management, respiratory support for patients with pneumonia or respiratory distress, fluid management for patients who cannot maintain adequate fluid intake, and volume resuscitation and/or vasopressor support for severely ill patients with signs of poor perfusion or septic shock. (See 'Supportive care' above.)

●Empiric therapy – The choice of empiric therapy for suspected SAB in children depends on the source and severity of the infection, whether the infection is community or health care associated, and, if community-associated, what the prevalence of methicillin-resistant S. aureus (MRSA) is in the community (table 1). In communities where MRSA accounts for >10 percent of the S. aureus isolates, empiric therapy should include coverage for MRSA. (See 'Empiric therapy' above.)

●Definitive therapy

•Antibiotic regimen – Once susceptibilities have been determined, the antimicrobial regimen can be modified. Most cases of confirmed invasive MRSA infections are initially treated with vancomycin (table 2). Intravenous nafcillin, oxacillin, or cefazolin are the antibiotics of choice when treating bacteremia caused by methicillin-susceptible S. aureus (MSSA) (table 3). (See 'Definitive therapy' above and "Staphylococcus aureus in children: Overview of treatment of invasive infections", section on 'Definitive antimicrobial therapy'.)

•Duration of therapy – The duration of therapy for SAB depends upon the source of infection (see 'Duration of therapy' above):

-No source identified – Parenteral therapy for 10 to 14 days generally is adequate for uncomplicated SAB in otherwise healthy children older than one month if no source is identified.

-Osteomyelitis or septic arthritis – SAB associated with osteomyelitis or septic arthritis is usually treated for at least three weeks. The initial treatment is with parenteral antibiotics; most patients can transition to oral antibiotics once they have clinically improved. (See "Bacterial arthritis: Treatment and outcome in infants and children", section on 'Total duration' and "Hematogenous osteomyelitis in children: Management", section on 'Total duration'.)

-Skin and soft tissue infection – SAB associated with skin and soft tissue infection is usually treated for 7 to 10 days. Patients can be transitioned to oral antibiotics 48 to 72 hours after blood cultures have become negative. (See "Skin and soft tissue infections in children >28 days: Evaluation and management", section on 'Total duration'.)

-Catheter-related infection – Catheter-related SAB is treated with 10 to 14 days of parenteral antibiotics.

-Infective endocarditis – S. aureus infective endocarditis is treated parenterally for a minimum of four to six weeks. (See "Infective endocarditis in children", section on 'Treatment'.)

●Monitoring

•Repeat blood cultures – Blood cultures should be repeated every 24 to 48 hours until two consecutive blood cultures are sterile and the patient is stable. Positive cultures persisting beyond 72 hours should prompt evaluations for unidentified foci of infection, such as septic thrombophlebitis, infective endocarditis, or undrained abscess. A complete blood count should be monitored weekly for patients receiving beta-lactam antibiotics. (See 'Repeat blood cultures' above.)

•Echocardiography – Echocardiography should be performed in children with SAB who have any of the following (see 'Echocardiography' above):

-Underlying congenital heart or valve disease

-Bacteremia lasting >2 to 3 days

-Clinical findings suggestive of endocarditis (eg, new or changing murmur, septic emboli)

●Outcome – The mortality associated with SAB in children is approximately 2 to 3 percent. The risk of mortality is increased in infants <1 year of age and in children with pulmonary infection, endocarditis, hospital-acquired infections, and comorbid conditions. (See 'Outcome' above.)