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Staphylococcus aureus in children: Overview of treatment of invasive infections

Staphylococcus aureus in children: Overview of treatment of invasive infections
Author:
Sheldon L Kaplan, MD
Section Editor:
Morven S Edwards, MD
Deputy Editor:
Mary M Torchia, MD
Literature review current through: Apr 2022. | This topic last updated: Feb 09, 2022.

INTRODUCTION — Staphylococcus aureus is a leading cause of both community-associated and health care-associated invasive infections in children.

An overview of the treatment of invasive infections caused by S. aureus in infants, children, and adolescents will be provided here. The genetic mechanisms responsible for methicillin resistance; the epidemiology, prevention, and control of methicillin-resistant S. aureus (MRSA) infections in children; and the treatment of MRSA skin and soft-tissue infections in infants and children are discussed separately.

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

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

(See "Suspected Staphylococcus aureus and streptococcal skin and soft tissue infections in neonates: Evaluation and management".)

(See "Suspected Staphylococcus aureus and streptococcal skin and soft tissue infections in children >28 days: Evaluation and management".)

MRSA, vancomycin-intermediate S. aureus (VISA), and vancomycin-resistant S. aureus (VRSA) infections in adults also are discussed separately.

(See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of bacteremia".)

(See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of skin and soft tissue infections".)

(See "Staphylococcus aureus bacteremia with reduced susceptibility to vancomycin".)

DEFINITIONS

Invasive infection – Infection of a normally sterile body site; invasive infections commonly associated with S. aureus include osteomyelitis, septic arthritis, pneumonia, visceral abscess, endocarditis, bacteremia (whether or not associated with a foreign body), and central nervous system infections (eg, cerebrospinal fluid shunt infection, epidural or subdural empyema, brain abscess)

Methicillin-susceptible S. aureusS. aureus isolate with an oxacillin minimum inhibitory concentration (MIC) ≤2 mcg/mL

Methicillin-resistant S. aureusS. aureus isolate with an oxacillin MIC ≥4 mcg/mL

Vancomycin susceptible S. aureusS. aureus isolate with a vancomycin MIC ≤2 mcg/mL

Vancomycin-intermediate S. aureusS. aureus isolate with a vancomycin MIC 4 through 8 mcg/mL

Vancomycin-resistant S. aureusS. aureus isolate with a vancomycin MIC ≥16 mcg/mL

PRETREATMENT EVALUATION — Specimens for culture and antimicrobial susceptibility testing should be collected whenever possible before initiation of antimicrobial therapy in children with invasive infections suspected to be caused by S. aureus given the limited number of antimicrobial agents with activity against methicillin-resistant S. aureus and the increasing emergence of multidrug-resistant strains [1]. Clinical features are not helpful in predicting methicillin or multidrug resistance.

All staphylococci isolated from normally sterile sites should undergo quantitative antimicrobial susceptibility testing (to beta-lactam antibiotics [eg, penicillins, cephalosporins], gentamicin, trimethoprim-sulfamethoxazole, tetracyclines, erythromycin, clindamycin, rifampin, vancomycin, linezolid, and possibly daptomycin) and testing for clindamycin-inducible resistance [2-4].

INDICATIONS FOR CONSULTATION — Consultation with an expert in infectious diseases may be warranted [4,5]:

For children with life-threatening infections (eg, sepsis, central nervous system infection, endocarditis, endovascular infection, infection complicated by venous thrombosis, pneumonia complicating influenza)

For guidance regarding choice of antimicrobial therapy (including combination antimicrobial therapy) and duration of therapy

Before use of linezolid, ceftaroline, daptomycin, or quinupristin-dalfopristin (because experience with these agents in children is limited)

For children with vancomycin-intermediate S. aureus or vancomycin-resistant S. aureus infections

For children who fail to respond to treatment with an agent to which their isolate is susceptible in vitro

REMOVAL OF INFECTIOUS FOCI — Management of invasive S. aureus infection usually requires removal of potential foci of infection (eg, intravascular catheters, purulent collections) [5-7]. Indications for removal of intravascular catheters and surgical drainage of purulent collections are discussed separately:

Intravascular catheter removal (see "Staphylococcus aureus bacteremia in children: Management and outcome", section on 'Intravascular catheter removal')

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')

Removal of implants (eg, spinal instrumentation, pacemaker, cochlear implant, baclofen pump, prosthetic joint) is often required for successful treatment of implant-associated S. aureus infections [8,9]. However, successful treatment with implant retention has been described with a combination of antimicrobial therapy, debridement, and surgical irrigation, particularly if the infection occurs within 90 days of placement [8,10,11].

EMPIRIC ANTIMICROBIAL THERAPY

When to suspect S. aureus infection — In most cases, S. aureus infection is suspected because there are clinical findings suggestive of a clinical syndrome or focal source that is associated with S. aureus infection. Less commonly, S. aureus is suspected because of underlying risk factors or Gram stain demonstrating gram-positive cocci in clusters (picture 1).

Clinical syndromes associated with S. aureus – Clinical syndromes in children that are commonly caused by S. aureus are listed below. Empiric therapy for these syndromes is discussed separately. It typically includes coverage for S. aureus and also may include coverage for non-staphylococcal pathogens.

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')

Necrotizing pneumonia, health care-associated pneumonia, pneumonia complicated by empyema, pneumonia complicating influenza or measles, aspiration pneumonia if the child's respiratory tract is colonized with S. aureus (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' and "Seasonal influenza in children: Management", section on 'Management of coinfection')

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

Bacteremia (see "Staphylococcus aureus bacteremia in children: Management and outcome", section on 'Empiric therapy')

Intravascular catheter infection (see "Intravascular non-hemodialysis catheter-related infection: Treatment")

Cerebrospinal fluid shunt infection (see "Infections of cerebrospinal fluid shunts and other devices", section on 'Empiric therapy')

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

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

Risk factors for invasive S. aureus infection – Although most children with invasive S. aureus infections are normal hosts, risk factors for invasive S. aureus infection include [4]:

Foreign body (eg, intravascular catheter or graft, peritoneal catheter, cerebrospinal fluid shunt, cardiovascular implantable electronic device, spinal instrumentation or intramedullary rod, cochlear implant, baclofen pump, prosthetic joint)

Preceding influenza or measles infection (see "Seasonal influenza in children: Clinical features and diagnosis", section on 'S. pneumoniae or S. aureus coinfection' and "Measles: Clinical manifestations, diagnosis, treatment, and prevention", section on 'Pulmonary')

Malignancy

Prematurity

Immunodeficiency or immunocompromised host (eg, those with phagocyte deficiency or dysfunction, HIV infection)

Diabetes mellitus

Choice of therapy — We hospitalize children with invasive infections that are suspected to be due to S. aureus and provide initial treatment with intravenous (IV) antimicrobial agents [4].

The choice of empiric parenteral therapy for suspected invasive S. aureus infection in children depends upon the site and severity of the infection, whether infection is health care-associated, the community prevalence of methicillin-resistant S. aureus (MRSA) infection, and local susceptibility patterns (table 1) [1,4]. Information regarding local susceptibility patterns can be obtained from local public health officials or hospital laboratories. Final therapy decisions should be based upon results of cultures and susceptibility testing. (See 'Definitive antimicrobial therapy' below.)

Clinical trials evaluating antimicrobial agents for invasive S. aureus infections in children are limited. Our treatment approach is based on case series, in vitro susceptibility testing, and the clinical experience of experts [1,4]. It is generally consistent with the recommendations of the American Academy of Pediatrics [4] and the Infectious Diseases Society of America [1].

Life-threatening infection (health care- or community-associated) – Life-threatening infections include sepsis, central nervous system infections (eg, meningitis, brain abscess, subdural empyema, spinal epidural abscess, septic thrombosis of cavernous or dural venous sinus), endocarditis, endovascular infection, infection complicated by venous thrombosis, and pneumonia complicating influenza. For children with life-threatening infections suspected to be caused by S. aureus, we provide initial treatment with vancomycin plus either nafcillin or oxacillin [4,12].

We suggest the following doses:

Vancomycin – For children ≤18 years of age, we use an initial dose of 15 mg/kg IV every six hours (maximum daily dose 4 g/day) [13]. Alternative dosing is suggested for clinicians/institutions who use area under the curve (AUC)-guided therapeutic monitoring for vancomycin for serious MRSA infections as suggested by consensus guidelines [14]; this strategy requires input from a clinical pharmacist, who will provide recommendations for initial dosing (table 2). (See 'Therapeutic monitoring for vancomycin' below.)

Nafcillin or oxacillin 37.5 to 50 mg/kg IV every six hours (maximum daily dose 12 g/day)

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

For empiric treatment of suspected MRSA pneumonia complicating influenza, we add a second anti-MRSA (eg, clindamycin, ceftaroline, linezolid) to vancomycin and anti-influenza therapy. Addition of a second anti-MRSA agent within the first 24 hours of admission may be associated with decreased mortality [15,16]. Monotherapy with ceftaroline is an alternative [17]. (See "Seasonal influenza in children: Management", section on 'Antiviral therapy'.)

The combination of vancomycin plus nafcillin or oxacillin is recommended to maximize activity against both MRSA and methicillin-susceptible S. aureus. Although other antimicrobial agents have activity against MRSA (eg linezolid, ceftaroline) [18,19], we prefer vancomycin given its efficacy and relative safety profile. We also have more clinical experience with vancomycin in treating a variety of invasive clinical syndromes (eg, pneumonia, meningitis).

Alternative regimens for children who cannot tolerate vancomycin (or are receiving other potentially nephrotoxic drugs) and/or penicillin antibiotics depend upon the clinical scenario:

For children without pneumonia, single drug therapy with daptomycin, ceftaroline, or linezolid is an alternative.

For children with pneumonia, single-drug therapy with linezolid or ceftaroline is an alternative.

For children who receive ceftaroline for antistaphylococcal activity and also need activity against gram-negative pathogens, we avoid third- or fourth-generation cephalosporins to prevent confusion in the event of a rash or other adverse reaction. Alternative agents for empiric gram-negative activity include aztreonam or levofloxacin. Local antibiotic susceptibility reports help guide selection.

Consultation with an expert in infectious diseases is recommended because experience with daptomycin, linezolid, and ceftaroline in children is limited [1,4,5,17,20-23]. Linezolid has the advantage that it is well absorbed orally, so therapy can be completed orally (when clinically appropriate) [2]. (See 'Indications for consultation' above.)

Nonlife-threatening health care-associated infection – For children with nonlife-threatening infections (ie, no signs of sepsis) that are suspected to be caused by health care-associated S. aureus, we provide initial treatment with vancomycin 15 mg/kg IV every six to eight hours (maximum daily dose 4 g) (table 2) [12]. S. aureus isolates from children with risk factors for health care-associated S. aureus are more likely to be resistant to clindamycin and other drugs than isolates from children without risk factors [24,25].

Risk factors for health care-associated S. aureus infection include personal history of or frequent contact with an individual with a history of hospitalization, surgery, dialysis, or residence in a long-term care facility within the previous year, frequent contact with the health care environment, presence of an invasive device (eg, intravascular catheter or tracheal tube), and history of MRSA infection or colonization. (See "Methicillin-resistant Staphylococcus aureus infections in children: Epidemiology and clinical spectrum", section on 'Epidemiology and risk factors'.)

Nonlife-threatening community-associated infection – For children with nonlife-threatening infections (ie, no signs of sepsis) that are suspected to be caused by community-associated S. aureus, empiric antimicrobial therapy depends upon the prevalence of MRSA in the community:

High prevalence of MRSA

-High prevalence of clindamycin resistance – In communities where MRSA accounts for >10 percent of community S. aureus isolates and the prevalence of clindamycin resistance is high (eg, ≥15 percent), we provide initial empiric therapy with vancomycin 15 mg/kg IV every six to eight hours (maximum daily dose 4 g) (table 2) [4,12]. For skin and soft tissue infections, trimethoprim (TMP)-sulfamethoxazole (20 mg TMP/kg/day in divided doses every six hours intravenously) is another option.

-Low prevalence of clindamycin resistance – In communities where MRSA accounts for >10 percent of community S. aureus isolates and the prevalence of clindamycin resistance is low (eg, <15 percent), we provide initial empiric therapy with clindamycin 40 mg/kg per day IV divided in three or four doses (maximum daily dose 2.7 g/day) if bacteremia is not likely [2,4,12].

Clindamycin should not be used for empiric treatment of invasive infections in communities with high rates of clindamycin resistance (constitutive plus inducible), as treatment failures have occurred [26-28]. The threshold prevalence of clindamycin-resistant MRSA (constitutive plus inducible) for choosing vancomycin varies from center to center, usually ranging from 10 to 25 percent, in an effort to balance the benefit of definitive therapy for the patient with the risk of increasing vancomycin resistance in the community. Additional considerations in the decision to choose vancomycin include the prevalence of MRSA in the community, the severity of illness, renal function and/or use of other nephrotoxic agents, and the turn-around time for susceptibilities.

Most community-associated MRSA (CA-MRSA) strains are susceptible to non-beta-lactam antibiotics (eg, clindamycin, trimethoprim-sulfamethoxazole) [29-32]. However, there is variability among CA-MRSA strains. Some are resistant to multiple drugs and some have susceptibility patterns similar to health care-associated MRSA isolates [26,27,33-35].

Low prevalence of MRSA – In communities where MRSA accounts for <10 percent of community S. aureus isolates, nafcillin or oxacillin 150 to 200 mg/kg per day IV in four doses (maximum daily dose 12 g/day) may be used for empiric therapy [12].

DEFINITIVE ANTIMICROBIAL THERAPY — Definitive antimicrobial therapy is determined by culture and susceptibility results.

MSSA infection

Central nervous system infection – Treatment of methicillin-susceptible S. aureus (MSSA) central nervous system (CNS) infections is discussed separately. (See "Bacterial meningitis in children older than one month: Treatment and prognosis", section on 'Specific therapy'.)

Infection outside the CNS – For the treatment of MSSA infections outside the CNS, we prefer one of the following regimens (table 3) [4,12,36]:

Nafcillin or oxacillin 150 to 200 mg/kg per day IV in four doses (maximum daily dose 12 g/day)

Cefazolin 100 mg/kg per day IV in three doses (maximum daily dose 6 g/day); for bone and joint infections, the dose may be increased up to 150 mg/kg per day IV in three or four doses (safety data are limited)

Nafcillin, oxacillin, and cefazolin are more effective than vancomycin for the treatment of MSSA [37-39]. Some MSSA isolates demonstrate higher minimum inhibitory concentrations (MICs) to cefazolin when tested at a higher inoculum (107cfu/mL) compared with the standard inoculum density (105 cfu/mL), the so-called "cefazolin inoculum effect" (CIE). The clinical implications for using cefazolin to treat children with an invasive MSSA infection due to an isolate demonstrating this effect is unclear [40]. CIE is only determined in research laboratories.

In addition to antistaphylococcal therapy, adjunctive antimicrobial therapy may be warranted for children with prosthetic valve endocarditis or other device-related infection (eg, spinal instrumentation, cardiovascular implantable electronic device (CIED), cochlear implant, baclofen pump, prosthetic joint). (See 'Adjunctive therapy for device-related infections' below.)

For children with MSSA infections outside the CNS who are unable to tolerate penicillin and cephalosporin antibiotics, we use [4]:

Clindamycin 40 mg/kg per day IV in three or four doses (maximum daily dose 2.7 g/day) if the isolate is clindamycin susceptible and the child does not have endocarditis or ongoing bacteremia, or

Vancomycin 60 mg/kg per day IV in four doses (maximum daily dose 4 g/day) (table 2)

Polymicrobial infection – For children with polymicrobial infections that include MSSA, ampicillin-sulbactam can be used alone if the non-S. aureus isolates are susceptible. Alternative agents for monotherapy for susceptible isolates include cefazolin and piperacillin-tazobactam.

MRSA infections — Methicillin resistance in S. aureus is defined as an oxacillin MIC ≥4 mcg/mL. Isolates resistant to oxacillin or methicillin are resistant to other beta-lactam agents, including cephalosporins (with the exception of ceftaroline and ceftobiprole). Definitive therapy for invasive methicillin-resistant S. aureus (MRSA) infections depends upon the type of infection, susceptibility of the isolate, and results of testing for inducible resistance to clindamycin (table 4) [1,4].

Health care-associated MRSA — For children with invasive health care-associated MRSA infections, we prefer vancomycin 15 mg/kg IV every six hours (maximum daily dose 4 g/day) (table 2) to other antistaphylococcal agents (table 4) [4,12]. We prefer vancomycin because of its efficacy and relative safety, and because we have more clinical experience with vancomycin in treating a variety of invasive MRSA infections.

In addition to antistaphylococcal therapy, adjunctive antimicrobial therapy may be warranted for children with prosthetic valve endocarditis or other device-related infection (eg, spinal instrumentation, pacemaker, cochlear implant, baclofen pump, prosthetic joint). (See 'Adjunctive therapy for device-related infections' below.)

For children who cannot tolerate vancomycin or for whom nephrotoxicity is a concern, consultation with an expert in infectious diseases is recommended. The preferred agent varies with susceptibility and clinical features including the site of infection. Possibilities include linezolid, daptomycin (except in children with pneumonia), ceftaroline, and trimethoprim-sulfamethoxazole (TMP-SMX) (table 4). Alternatives to vancomycin for CNS infections include linezolid, daptomycin, and TMP-SMX [41].

TMP-SMX and linezolid have the advantage of oral formulations, so that therapy can be completed orally (when clinically appropriate) [2]. Consultation with an expert in infectious diseases is suggested before use of linezolid, ceftaroline, or daptomycin because clinical experience with these agents in children is limited [4,42,43]. (See 'Indications for consultation' above.)

Experience with linezolid for the treatment of staphylococcal infections in children is limited, but growing [44-46]. In subgroup analysis of a randomized trial, among children hospitalized with MRSA pneumonia, bacteremia, or complicated skin infection, clinical and microbiologic cure rates were approximately 90 percent for both linezolid and vancomycin [46].

Published experience with ceftaroline and daptomycin in children with invasive MRSA infections is limited, but growing [47-50].

There are no randomized studies evaluating TMP-SMX for the treatment of invasive MRSA infections in children. In randomized trials in adults, TMP-SMX has been less effective than vancomycin for the treatment of serious MRSA infections [51,52]. However, in one trial, bacteriologic cure was achieved in 86 percent of patients with serious MRSA infection (compared with 98 percent for vancomycin) [51].

Community-associated MRSA

Life-threatening infection – Life-threatening infections include sepsis, central nervous system infections, endocarditis, endovascular infection, infection complicated by venous thrombosis, and pneumonia complicating influenza. Vancomycin 15 mg/kg IV every six hours (maximum daily dose 4 g) (table 2) is preferred for the treatment of life-threatening community-associated MRSA (CA-MRSA) infections [4,12].

For pneumonia complicating influenza, we add a second anti-MRSA (eg, clindamycin, ceftaroline, linezolid) to vancomycin and anti-influenza therapy. Addition of a second anti-MRSA agent within the first 24 hours of admission may be associated with decreased mortality [15,16]. Ceftaroline monotherapy is another option for pneumonia complicating influenza [17]. (See "Seasonal influenza in children: Management", section on 'Antiviral therapy'.)

In addition to antistaphylococcal therapy, adjunctive antimicrobial therapy may be warranted for children with prosthetic valve endocarditis or other device-related infection (eg, spinal instrumentation, pacemaker, cochlear implant, baclofen pump, prosthetic joint). (See 'Adjunctive therapy for device-related infections' below.)

Consultation with an expert in infectious diseases is recommended if vancomycin cannot be administered (eg, for children with renal dysfunction). Alternatives to vancomycin include ceftaroline, daptomycin, or linezolid. Ceftaroline or daptomycin are preferred to linezolid because cases of apparent failure of linezolid to treat or prevent endocarditis in patients with intravascular MRSA infection have been described [53-55]. Linezolid is well absorbed orally, so therapy can be completed orally (when clinically appropriate) [2].

Pneumonia, septic arthritis, or osteomyelitis – For the treatment of CA-MRSA septic arthritis, osteomyelitis, or pneumonia without concomitant influenza, we prefer clindamycin 40 mg/kg per day in three or four doses (maximum daily dose 2.7 g/day) if the isolate is susceptible [4,12]. Clindamycin is well absorbed orally, so therapy can be completed orally (when clinically appropriate) [2]. In retrospective observational studies, clindamycin has been effective in the treatment of CA-MRSA infections in children [56,57].

For children with pneumonia, linezolid or ceftaroline is an option if the isolate is resistant to clindamycin (table 4). Daptomycin should not be used for treatment of pneumonia because its activity is inhibited by pulmonary surfactant [58,59].

For children with septic arthritis or osteomyelitis, vancomycin, linezolid, daptomycin, or ceftaroline are options if the isolate is resistant to clindamycin (table 4) [1]. (See "Bacterial arthritis: Treatment and outcome in infants and children", section on 'Pathogen-directed therapy' and "Hematogenous osteomyelitis in children: Management", section on 'Pathogen-directed therapy'.)

Consultation with an expert in infectious diseases is suggested before use of linezolid, daptomycin, or ceftaroline because clinical experience with these agents in children is lacking.

Experience with linezolid for the treatment of serious staphylococcal infections in children is limited, but growing [19,44-46]. In a randomized trial in 321 hospitalized children (0 to 11 years) with gram-positive pneumonia, bacteremia, or complicated skin infections, overall clinical cure rates were similar among children treated with linezolid and vancomycin (79 and 74 percent, respectively) [19]. Among children with MRSA, clinical cure rates were 94 and 90 percent, and bacteriologic cure rates were 88 and 90 percent, respectively [46]. Similar findings have been reported in adults [18].

Daptomycin and ceftaroline have activity against MRSA, as well as against other resistant gram-positive bacteria [58,60,61].

Serious skin and soft tissue infections – The management of serious MRSA skin and soft tissue infections (SSTIs) in children, including MRSA SSTIs that require hospitalization, is discussed separately. (See "Suspected Staphylococcus aureus and streptococcal skin and soft tissue infections in neonates: Evaluation and management", section on 'SSTI more severe than localized pustulosis' and "Suspected Staphylococcus aureus and streptococcal skin and soft tissue infections in children >28 days: Evaluation and management", section on 'Systemic antimicrobial therapy'.)

Adjunctive therapy for device-related infections — For children with prosthetic valve endocarditis or other device-related infections, we add gentamicin and/or rifampin to antistaphylococcal therapy as follows:

Prosthetic valve endocarditis – For S. aureus prosthetic valve endocarditis, we add gentamicin 1 mg/kg three times per day IV and rifampin 10 mg/kg orally or IV twice per day (maximum daily dose 600 mg) for the first two weeks of treatment [1,62]. (See "Antimicrobial therapy of prosthetic valve endocarditis", section on 'Staphylococci'.)

Other device-related infections – For children with other device-related S. aureus infections (eg, spinal instrumentation, CIED, cochlear implant, baclofen pump, prosthetic joint), we add rifampin 10 mg/kg orally or IV twice per day (maximum daily dose 600 mg) for up to two months if rifampin is tolerated and the device remains in place.

VISA infections — Vancomycin-intermediate S. aureus (VISA) is defined as a vancomycin MIC 4 to 8 mcg/mL [63,64]. VISA isolates have been rarely reported in children [65]. Consultation with an expert in infectious diseases is suggested in the management of children with VISA infections [4]. Optimal therapy for VISA infections in children has yet to be determined.

The choice of antibiotic depends upon the results of in vitro susceptibility studies. For children with a susceptible isolate, we prefer one of the following regimens if the isolate is susceptible [4,12,66]:

Linezolid

<12 years: 30 mg/kg intravenously (IV) per day in three doses

≥12 years: 600 mg IV twice per day

Ceftaroline 15 mg/kg per dose IV (administered over 2 hours) every eight hours; maximum dose 600 mg

Daptomycin (except for children with pneumonia)

1 through 6 years: 12 mg/kg IV once daily

7 through 11 years: 9 mg/kg IV once daily

12 through 17 years: 7 mg/kg IV once daily

Quinupristin-dalfopristin 7.5 mg/kg per dose IV three times per day (requires central venous access)

Alternative regimens include vancomycin combined with linezolid (with or without gentamicin) or vancomycin combined with TMP-SMX [4]. We add gentamicin and rifampin for the first two weeks of treatment of prosthetic valve endocarditis. We add rifampin for the treatment of other device-related infections (eg, spinal instrumentation, prosthetic joint).

VRSA infections — Vancomycin-resistant S. aureus (VRSA) is defined as a vancomycin MIC ≥16 mcg/mL [63,64]. VRSA isolates have been rarely reported in children [65]. VRSA strains have been susceptible to several other agents, including linezolid, quinupristin-dalfopristin, daptomycin, and ceftaroline [67-71]. Consultation with an expert in pediatric infectious diseases is suggested in the management of children with VRSA infections. (See "Staphylococcus aureus bacteremia with reduced susceptibility to vancomycin".)

THERAPEUTIC MONITORING FOR VANCOMYCIN

Indications — The indications for therapeutic monitoring for vancomycin may vary from institution to institution. We routinely perform therapeutic monitoring for vancomycin in children with renal dysfunction, infective endocarditis, and children with risk factors for altered vancomycin kinetics (eg, fluid overload, critical illness).

For children with other serious staphylococcal infections (eg, pneumonia requiring hospitalization, osteomyelitis, central nervous system infection), we make decisions about therapeutic monitoring on a case-by-case basis, considering the anticipated duration of vancomycin therapy and other clinical factors (eg, additional nephrotoxic drugs).

Choice of strategy — There are two methods of therapeutic monitoring for vancomycin: trough-guided dosing and area under the curve (AUC)-guided dosing, which requires the assistance of a clinical pharmacist (table 2). The preferred approach may vary from facility to facility.

We generally favor trough-guided monitoring. Although AUC-guided dosing is suggested by consensus guidelines [14], the advantages and feasibility of this approach for most pediatric facilities remain to be determined [13,72].

Trough-guided dosing – When indicated, we usually obtain vancomycin trough concentrations immediately before the third or fourth dose of vancomycin. We aim to achieve trough concentrations of 5 to 15 mcg/mL and extend the dosing interval if the trough is ≥15 mcg/mL [14]. In one report, vancomycin trough levels <10 mcg/mL within the first 72 hours of treatment were associated with a longer duration of MRSA bacteremia [50]. Although trough concentrations ≥15 mcg/mL have been recommended for adult patients [1,73], in observational studies in children, trough concentrations ≥15 mcg/mL have not been associated with improved outcomes and have been associated with increased risk of acute kidney injury [74-77].

Once the target trough has been achieved, we continue to monitor trough concentrations in children with abnormal renal function after one or several subsequent doses to monitor the dosing interval; we consult a clinical pharmacist as necessary for guidance. For children whose renal function has returned to normal and whose vancomycin course will be prolonged (eg, >2 weeks), we monitor trough concentrations every 7 to 10 days.

AUC-guided dosing – In the AUC-guided approach, the vancomycin dose is adjusted based on the ratio of the AUC over 24 hours to the minimum inhibitory concentration (AUC/MIC) [14]. Clinical pharmacists can use software programs to estimate the AUC/MIC from serum peak and trough vancomycin levels ideally obtained within 24 to 48 hours of initiation of treatment. The target AUC/MIC is 400, assuming a vancomycin MIC of 1 mg/L.

Additional details of AUC-guided dosing for children are provided in the consensus guideline [14]. (See 'Society guideline links' below.)

DURATION OF THERAPY — The duration of therapy for invasive S. aureus infection depends upon the site but usually is at least four weeks for endocarditis, osteomyelitis, necrotizing pneumonia, and disseminated infection, provided that the child responds clinically and microbiologically [4].

Parenteral therapy is recommended for the entire course in patients with endocarditis and central nervous system infections. Oral therapy may be used for a portion of the course in patients with other types of infection.

Duration of therapy and criteria for switching to oral therapy for specific clinical syndromes are discussed separately.

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

Osteomyelitis (see "Hematogenous osteomyelitis in children: Management", section on 'Total duration')

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

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

Bacterial meningitis (see "Bacterial meningitis in children older than one month: Treatment and prognosis", section on 'Treatment duration')

Sepsis (see "Septic shock in children: Ongoing management after resuscitation", section on 'Eradicate infection')

Toxic shock syndrome (see "Staphylococcal toxic shock syndrome", section on 'Duration of therapy')

Bacteremia (see "Staphylococcus aureus bacteremia in children: Management and outcome", section on 'Duration of therapy')

Intravascular catheter infection (see "Intravascular non-hemodialysis catheter-related infection: Treatment")

TREATMENT OF NEONATES — We hospitalize infants ≤28 days who have been evaluated for invasive infection and provide the entire course of antimicrobial therapy parenterally [78]. (See "The febrile infant (29 to 90 days of age): Outpatient evaluation" and "The febrile infant (29 to 90 days of age): Management".)

Empiric antimicrobial therapy for S. aureus infection in neonates should be based upon the local susceptibility pattern of community-associated S. aureus isolates. Information regarding local susceptibility patterns can be obtained from local public health officials or hospital laboratories. The author's institution uses vancomycin, nafcillin, and gentamicin for neonates with suspected invasive staphylococcal infection (table 5). Gentamicin is included to cover possible gram-negative enteric pathogens.

If methicillin-resistant S. aureus (MRSA) infection is confirmed, intravenous vancomycin is preferred [1]; clindamycin or linezolid are alternatives for nonendovascular MRSA infections [4]. Linezolid should be used in consultation with an expert in infectious diseases. The doses of the suggested antimicrobial agents are provided in the table (table 5). Our recommendations are generally consistent with the Infectious Diseases Society of America guidance for the management of invasive MRSA infections in infants (≤28 days of age) [1], which are based upon observations from a single-institution review of 126 cases treated between 2001 and 2006 [78].

In a randomized trial in 63 neonates hospitalized with known or suspected resistant gram-positive infections, clinical and microbiologic cure rates were similar with linezolid and vancomycin [45]; S. aureus accounted for 12 of 50 infections with a known pathogen.

General aspects of management of invasive infections in neonates are discussed separately. (See "Bacterial meningitis in the neonate: Treatment and outcome" and "Urinary tract infections in neonates" and "Neonatal pneumonia" and "Suspected Staphylococcus aureus and streptococcal skin and soft tissue infections in neonates: Evaluation and management".)

TREATMENT FAILURE — Some patients with invasive S. aureus infections fail to respond to treatment with an agent to which their isolate is susceptible in vitro [5]. Potential reasons for this include:

Poor source control (eg, loculated parapneumonic effusion, incomplete drainage of abscesses, infected device remains in place)

Reduced antimicrobial concentration at the site of infection [79-81]

Heteroresistance to vancomycin (eg, subpopulations of organisms with reduced susceptibility) (see "Overview of antibacterial susceptibility testing", section on 'Heteroresistance')

Strategies to overcome these problems include the addition of adjunctive antimicrobial agents (eg, rifampin, gentamicin) and/or a change in antimicrobial therapy [1,82]. In either case, consultation with an expert in pediatric infectious diseases is recommended.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Management of Staphylococcus aureus infection".)

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 5th to 6th 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 10th to 12th 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.)

Beyond the Basics topics (see "Patient education: Methicillin-resistant Staphylococcus aureus (MRSA) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Specimens for culture and antimicrobial susceptibility testing should be collected whenever possible before initiation of antimicrobial therapy in children with invasive infections suspected to be caused by Staphylococcus aureus. All staphylococci isolated from normally sterile sites should undergo quantitative antimicrobial susceptibility and testing for clindamycin-inducible resistance. (See 'Pretreatment evaluation' above.)

Management of invasive S. aureus infection usually requires removal of potential foci of infection (eg, intravascular catheters, purulent collections). (See 'Removal of infectious foci' above.)

In most cases, invasive S. aureus infection is suspected because there are clinical findings suggestive of a clinical syndrome or focal source that is associated with S. aureus infection (eg, osteomyelitis, septic arthritis, pneumonia, infective endocarditis, foreign body-associated bacteremia). Less commonly, S. aureus is suspected because of underlying risk factors (eg, diabetes mellitus, immunodeficiency) or Gram stain demonstrating gram-positive cocci in clusters. (See 'When to suspect S. aureus infection' above.)

We hospitalize children with invasive infections that are suspected to be due to S. aureus and provide initial treatment with intravenous antimicrobial agents. The choice of empiric therapy for suspected invasive S. aureus infection in children depends upon the site and severity of the infection, the community prevalence of methicillin-resistant S. aureus (MRSA) infection, and local susceptibility patterns (table 1). Additional antibiotics may be required for non-staphylococcal pathogens until the pathogen is identified. (See 'Empiric antimicrobial therapy' above.)

Definitive antimicrobial therapy for S. aureus infections is determined by culture and whether the isolate is methicillin-susceptible (table 3) or methicillin-resistant (table 4). (See 'Definitive antimicrobial therapy' above.)

The duration of therapy for invasive S. aureus infection depends upon the site of infection and clinical response to treatment. It is usually at least four weeks for endocarditis, osteomyelitis, necrotizing pneumonia, and disseminated infection, provided that the child responds clinically and microbiologically. Parenteral therapy is recommended for the entire course for children with endocarditis and central nervous system infections. Oral therapy may be used for a portion of the course in patients with other types of infection. (See 'Duration of therapy' above.)

We hospitalize infants ≤28 days who have been evaluated for invasive infection and provide the entire course of antimicrobial therapy parenterally. The author's institution uses vancomycin, nafcillin, and gentamicin for neonates with suspected invasive staphylococcal infection (table 5). If MRSA infection is confirmed, intravenous vancomycin is preferred; clindamycin or linezolid are alternatives for nonendovascular MRSA infections. (See 'Treatment of neonates' above.)

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