Methicillin-Resistant Staphylococcus aureus: A Pharmacotherapy Primer

      Key Words

      • 1.
        Recommend appropriate antimicrobial regimens for a given MRSA infection.
      • 2.
        Describe the mechanisms, dosing, and monitoring parameters of antibiotics used to treat MRSA infections.
      • 3.
        Explain the mechanisms and implications of antibiotic resistance among Staphylococcus aureus.
      Staphylococcus aureus is a common pathogen that can infect a variety of body sites, causing skin and soft tissue infections (SSTIs), bacteremia and endocarditis, bone and joint infections, pneumonia, and infections of the central nervous system (
      • Liu C.
      • Bayer A.
      • Cosgrove S.E.
      • Daum R.S.
      • Fridkin S.K.
      • Gorwitz R.J.
      • Chambers H.F.
      Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.
      ,
      • Lowy F.D.
      Staphylococcus aureus infections.
      ). A working knowledge of the management of S. aureus infections is important to provide prompt and optimal care, because S. aureus is associated with significant morbidity and mortality and is highly prevalent in both hospital and community settings, and because treatment involves a variety of antibiotics with different mechanisms and toxicities. Antibiotic selection for children is further complicated by unique toxicities and a relative lack of dosing guidance and supporting data.

      Microbiology and Epidemiology

      Staphylococci are Gram-positive cocci that grow most commonly in irregular clusters. All Staphylococcus species typically produce the enzyme catalase and are facultative anaerobes (
      • Que Y.
      • Moreillon P.
      Staphylococcus aureus (including staphylococcal toxic shock).
      ). S. aureus may be differentiated from other Staphylococcus species by its production of the enzyme coagulase and is referred to as “coagulase-positive.” Aside from S. aureus, all other staphylococci found in humans are coagulase-negative and, when pathogenic, are generally less virulent (
      • Que Y.
      • Moreillon P.
      Staphylococcus aureus (including staphylococcal toxic shock).
      ,
      • Rupp M.E.
      • Fey P.D.
      Staphylococcus epidermidis and other coagulase- negative staphylococci.
      ).
      S. aureus commonly colonizes skin and mucosa. Asymptomatic nasal colonization, occurring in approximately 30% of the population, has contributed to the spread and persistence of S. aureus (
      • Chambers H.F.
      • DeLeo F.R.
      Waves of resistance: Staphylococcus aureus in the antibiotic era.
      ). Such persistence, as well as enhanced pathogenesis, may also be attributed to a variety of microbiological factors. Surface adhesions and biofilm production promote adherence to host proteins and medical devices (
      • Que Y.
      • Moreillon P.
      Staphylococcus aureus (including staphylococcal toxic shock).
      ). Additionally, S. aureus produces a number of enzymes and toxins including hemolysins and the Panton-Valentine leukocidin that may be associated with more severe infections (
      • Chambers H.F.
      • DeLeo F.R.
      Waves of resistance: Staphylococcus aureus in the antibiotic era.
      ,
      • Que Y.
      • Moreillon P.
      Staphylococcus aureus (including staphylococcal toxic shock).
      ). Historically, all strains of S. aureus were susceptible to penicillin, but development of penicillin resistance, followed by methicillin resistance, spread during the 1970s and 1980s, followed by the substantial presence of methicillin-resistant S. aureus (MRSA) in both hospital and community settings by the 1990s (
      • Chambers H.F.
      • DeLeo F.R.
      Waves of resistance: Staphylococcus aureus in the antibiotic era.
      ,
      • Iwamoto M.
      • Mu Y.
      • Lynfield R.
      • Bulens S.N.
      • Nadle J.
      • Aragon D.
      • Lessa F.C.
      Trends in invasive methicillin-resistant Staphylococcus aureus infections.
      ). MRSA continues to represent a significant health care challenge today.

      Pharmacotherapy of Common MRSA infections

      Beyond the type of infection caused by MRSA, antibiotic selection also depends on the patient's overall clinical status and severity of infection. For example, MRSA SSTIs may range from uncomplicated impetigo likely to resolve without any antimicrobial therapy to a life-threatening extensive infection progressing to toxic shock needing broad-spectrum antibiotics. When managing bacteremia, a positive blood culture result alone is insufficient to guide antibiotic selection, and the source of the bloodstream infection must be considered. For example, rapidly resolving bacteremia attributable to an SSTI or acute hematogenous osteomyelitis (AHO) is treated differently than complicated bacteremia with an intravascular source of infection as in endocarditis. Although the following sections focus on pharmacotherapy, many nonpharmacologic interventions such as radiographic imaging, incision and drainage, removal of infected hardware, and identification and management of any predisposing conditions like immune system deficiencies are critical to successful treatment. Antibiotic options that may be suitable for each infection type reviewed below are also summarized in Box 1.
      When managing bacteremia, a positive blood culture result alone is insufficient to guide antibiotic selection…
      Antibiotic options for selected MRSA infections
      • Skin and skin structure infections
        • Clindamycin
        • SMX-TMP
        • Vancomycin
        • Linezolid
        • Ceftarolinea
        • Daptomycinb
        • Doxycyclinec
      • Osteomyelitis
        • Clindamycin
        • Vancomycin
        • Daptomycinb
        • Linezolid
      • Pneumonia
        • Vancomycin
        • Linezolid
        • Clindamycin
        • Ceftarolinea
      • CNS infection
        • Vancomycin
        • Linezolid
        • SMX-TMP
      • Bacteremia and infective endocarditis (IE)
        • Vancomycin (+rifampin + gentamicin for prosthetic valve IE)
        • Daptomycinb
        • Ceftarolinea
      Note. CNS, central nervous system; FDA, U.S. Food and Drug Administration; MRSA, methicillin-resistant Staphylococcus aureus; SMX-TMP, sulfamethoxazole/trimethoprim.
      aCeftaroline is approved only for use in skin and soft tissue infections and non-MRSA community acquired pneumonia.
      bNot FDA-approved for use in children.
      cAvoid use in children younger than 8 years of age.

      Skin and Soft Tissue Infections

      Purulent skin infection, or the presence of pus within an abscess or other wound, is suggestive of a staphylococcal infection, and drainage should be sent for culture and susceptibility testing. Current guidelines for SSTI management recommend topical mupirocin for bullous and nonbullous impetigo, but systemic therapy is recommended in the setting of an outbreak for patients with multiple lesions (
      • Stevens D.L.
      • Bisno A.L.
      • Chambers H.F.
      • Dellinger E.P.
      • Goldstein E.J.
      • Gorbach S.L.
      • Wade J.C.
      Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America.
      ). Systemic antibiotic therapy is additionally recommended for more complicated or extensive skin abscesses, including failure to improve after incision and drainage, associated septic phlebitis or spreading cellulitis, incomplete drainage, or systemic illness (
      • Liu C.
      • Bayer A.
      • Cosgrove S.E.
      • Daum R.S.
      • Fridkin S.K.
      • Gorwitz R.J.
      • Chambers H.F.
      Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.
      ). In the outpatient setting, a variety of oral antibiotics may be used for MRSA SSTIs, including sulfamethoxazole/trimethoprim (SMX-TMP), clindamycin, doxycycline, or linezolid. Antibiotic selection requires consideration of regional or institutional susceptibility patterns, patient age, and drug costs and toxicities. For example, doxycycline is not used in children under 8 years of age, and linezolid is more expensive than other treatment options. Drug-specific considerations are reviewed in greater detail later.
      Children hospitalized for a complicated SSTI should be treated with vancomycin, particularly in the setting of bacteremia, hemodynamic instability, or other signs of systemic illness. Clindamycin may also be used empirically for clinically stable patients without persistent bacteremia or endocarditis, if the institutional rate of clindamycin resistance among S. aureus is less than 10% to 15%.
      Staphylococcal scalded skin syndrome and toxic shock syndrome (TSS) are toxin-mediated disease states. Although TSS typically presents with a rash early and later desquamation, it is a multisystem illness, including hypotension and multiorgan failure. TSS has been associated with tampon use but may present in association with skin lesions or surgery, or without any clear infection source (
      ). In addition to supportive care measures like hydration and vasopressor therapy, prompt antibiotic treatment with a cell wall active agent, typically vancomycin, in combination with a protein synthesis inhibitor like clindamycin to reduce toxin production is critical (
      ).
      Because staphylococcal SSTIs often recur in patients and family members, there is interest in eradicating asymptomatic colonization or carriage of S. aureus as a means of reducing spread and continued infections (
      • Creech C.B.
      • Al-Zubeidi D.N.
      • Fritz S.A.
      Prevention of recurrent staphylococcal skin infections.
      ). This practice is referred to as decolonization, and it most often involves topical antimicrobial therapy including intranasal mupirocin and chlorhexidine washes (
      • Stevens D.L.
      • Bisno A.L.
      • Chambers H.F.
      • Dellinger E.P.
      • Goldstein E.J.
      • Gorbach S.L.
      • Wade J.C.
      Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America.
      ). Reported outcomes of topical MRSA decolonization are varied. Although most studies comparing decolonization to either placebo or standard hygiene practices identified greater S. aureus eradication in the treatment groups, the impact on later incidence of SSTI was varied and not consistently reduced among patients who had undergone decolonization (
      • Ellis M.W.
      • Griffith M.E.
      • Dooley D.P.
      • McLean J.C.
      • Jorgensen J.H.
      • Patterson J.E.
      • Hospenthal D.R.
      Targeted intranasal mupirocin to prevent colonization and infection by community-associated methicillin-resistant Staphylococcus aureus strains in soldiers: A cluster randomized controlled trial.
      ,
      • Fritz S.A.
      • Camins B.C.
      • Eisenstein K.A.
      • Fritz J.M.
      • Epplin E.K.
      • Burnham C.A.
      • Storch G.A.
      Effectiveness of measures to eradicate Staphylococcus aureus carriage in patients with community-associated skin and soft-tissue infections: A randomized trial.
      ,
      • Raz R.
      • Miron D.
      • Colodner R.
      • Staler Z.
      • Samara Z.
      • Keness Y.
      A 1-year trial of nasal mupirocin in the prevention of recurrent staphylococcal nasal colonization and skin infection.
      ,
      • Whitman T.J.
      • Herlihy R.K.
      • Schlett C.D.
      • Murray P.R.
      • Grandits G.A.
      • Ganesan A.
      • Tribble D.R.
      Chlorhexidine-impregnated cloths to prevent skin and soft-tissue infection in Marine recruits: A cluster-randomized, double-blind, controlled effectiveness trial.
      ). Additionally, later development of resistance to topical therapies has been reported (
      • Fritz S.A.
      • Hogan P.G.
      • Camins B.C.
      • Ainsworth A.J.
      • Patrick C.
      • Martin M.S.
      • Burnham C.A.
      Mupirocin and chlorhexidine resistance in Staphylococcus aureus in patients with community-onset skin and soft tissue infections.
      ,
      • McNeil J.C.
      • Hulten K.G.
      • Kaplan S.L.
      • Mason E.O.
      Mupirocin resistance in Staphylococcus aureus causing recurrent skin and soft tissue infections in children.
      ,
      • McNeil J.C.
      • Hulten K.G.
      • Kaplan S.L.
      • Mahoney D.H.
      • Mason E.O.
      Staphylococcus aureus infections in pediatric oncology patients: High rates of antimicrobial resistance, antiseptic tolerance and complications.
      ) but was not confirmed in a recent randomized controlled trial (
      • Hayden M.K.
      • Lolans K.
      • Haffenreffer K.
      • Avery T.R.
      • Kleinman K.
      • Li H.
      • Huang S.S.
      Chlorhexidine and mupirocin susceptibility of methicillin-resistant Staphylococcus aureus isolates in the REDUCE-MRSA trial.
      ). Consistent with existing literature and current national consensus guidelines, decolonization should be prioritized for patients with recurrent SSTIs or for settings where S. aureus is continually being spread among household members (
      • Creech C.B.
      • Al-Zubeidi D.N.
      • Fritz S.A.
      Prevention of recurrent staphylococcal skin infections.
      ,
      • Liu C.
      • Bayer A.
      • Cosgrove S.E.
      • Daum R.S.
      • Fridkin S.K.
      • Gorwitz R.J.
      • Chambers H.F.
      Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.
      ,
      • Stevens D.L.
      • Bisno A.L.
      • Chambers H.F.
      • Dellinger E.P.
      • Goldstein E.J.
      • Gorbach S.L.
      • Wade J.C.
      Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America.
      ).

      Pneumonia

      MRSA pneumonia is most commonly a health care–associated or hospital-acquired infection and is rarely implicated in community-acquired pneumonia (CAP). MRSA CAP has been described in association with previous or concurrent influenza and among patients with diabetes or those requiring hemodialysis (
      • Self W.H.
      • Wunderink R.G.
      • Williams D.J.
      • Zhu Y.
      • Anderson E.J.
      • Balk R.A.
      • Grijalva C.G.
      Staphylococcus aureus community-acquired pneumonia: prevalence, clinical characteristics, and outcomes.
      ). Although not confirmed in a recent case–control study to be unique to MRSA, it remains prudent to empirically cover MRSA in severe cases of CAP, such as patients requiring admission to an intensive care unit or presenting with empyema or cavitation on radiograph (
      • Liu C.
      • Bayer A.
      • Cosgrove S.E.
      • Daum R.S.
      • Fridkin S.K.
      • Gorwitz R.J.
      • Chambers H.F.
      Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.
      ,
      • Self W.H.
      • Wunderink R.G.
      • Williams D.J.
      • Zhu Y.
      • Anderson E.J.
      • Balk R.A.
      • Grijalva C.G.
      Staphylococcus aureus community-acquired pneumonia: prevalence, clinical characteristics, and outcomes.
      ). The recommended treatment of MRSA pneumonia in children is vancomycin, with the alternative option of clindamycin for clinically stable patients without persistent bacteremia at practice at sites where less than 10% of S. aureus are resistant to clindamycin. Other treatment options include linezolid or, potentially, ceftaroline. Recent consensus guidelines for the treatment of hospital-acquired pneumonia in adults recommend only vancomycin or linezolid for the empiric treatment of MRSA pneumonia (
      • Kalil A.C.
      • Metersky M.L.
      • Klompas M.
      • Muscedere J.
      • Sweeney D.A.
      • Palmer L.B.
      • Brozek J.L.
      Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society.
      ). Daptomycin serves no role in the management of pneumonia because it is inactivated by pulmonary surfactant (
      Merck & Co., Inc
      Cubicin [package insert].
      ). CAP in children is typically treated for 7 to 10 days, although longer treatment courses may be prescribed depending on the severity and improvement of the infection.

      Bone and Joint Infections

      Acute hematogenous osteomyelitis (AHO) is common in young children because of open epiphyses with capillaries providing nutrients to growing bones. A transient bacteremia can lead to a bone infection more easily in a child than in an adult (
      • Gutierrez K.
      Osteomyelitis.
      ). Osteomyelitis may also occur secondary to injury like an open fracture or puncture wound, or an untreated local infection such as a periodontal abscess progressing to facial osteomyelitis.
      In addition to surgical debridement when indicated (particularly in the setting of septic arthritis), treatment involves either vancomycin or clindamycin. Current guidelines recommend either vancomycin or clindamycin, with the same stipulations as described for clindamycin with respect to patient status, blood culture results, and institutional susceptibility data. Linezolid, SMX-TMP, and daptomycin are additional alternatives. Daptomycin is currently being studied for AHO in children, and investigational dosing regimens are reviewed later. The recommended duration of therapy for MRSA osteomyelitis is dependent on patient progress, often involving repeated imaging, monitoring of C-reactive protein concentrations, and evaluation of clinical response. At a minimum, septic arthritis is typically treated for 3 to 4 weeks and AHO for 4 to 6 weeks (
      • Erickson C.M.
      • Sue P.K.
      • Stewart K.
      • Thomas M.I.
      • Lindsay E.A.
      • Jo C.
      • Copley L.A.B.
      ,
      • Keren R.
      • Shah S.S.
      • Srivastava R.
      • Rangel S.
      • Bendel-Stenzel M.
      • Harik N.
      • Parker A.
      Comparative effectiveness of intravenous vs oral antibiotics for postdischarge treatment of acute osteomyelitis in children.
      ,
      • Liu C.
      • Bayer A.
      • Cosgrove S.E.
      • Daum R.S.
      • Fridkin S.K.
      • Gorwitz R.J.
      • Chambers H.F.
      Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.
      ). These prolonged durations of therapy may require long-term intravenous (IV) antibiotics, but equivalent outcomes have been observed after oral treatment with clindamycin (
      • Erickson C.M.
      • Sue P.K.
      • Stewart K.
      • Thomas M.I.
      • Lindsay E.A.
      • Jo C.
      • Copley L.A.B.
      ,
      • Keren R.
      • Shah S.S.
      • Srivastava R.
      • Rangel S.
      • Bendel-Stenzel M.
      • Harik N.
      • Parker A.
      Comparative effectiveness of intravenous vs oral antibiotics for postdischarge treatment of acute osteomyelitis in children.
      ) without the inconvenience or associated risks of IV treatment like thrombosis or infection.

      Bacteremia and Endocarditis

      Infections described earlier like SSTIs, pneumonia, or bone and joint infections may present with transient bacteremia, but bloodstream infections related to intravascular catheters or endovascular tissue represent unique disease states requiring different approaches to management.
      Bloodstream infections are a common complication of intravascular catheters, and management depends on characteristics of both the patient and the infected line. In contrast to abscesses, which can be promptly drained, or short-term catheter lines, which can be readily removed, source control is a more complicated treatment decision in the setting of long-term central venous IV catheters. Many children depend on this type of IV access for survival, such as those with short bowel syndrome requiring parenteral nutrition or those with renal failure requiring hemodialysis. In these patients, the availability and accessibility of alternative catheter insertion sites must be carefully considered in addition to patient, pathogen, and infection characteristics, and greater efforts to salvage catheters may be warranted. To retain an infected catheter, sterilization must be achieved through strategies like infusing IV antibiotics directly through the infected catheter or locking the IV line with antibiotics or ethanol (
      • Mermel L.A.
      • Allon M.
      • Bouza E.
      • Craven D.E.
      • Flynn P.
      • O'Grady N.P.
      • Warren D.K.
      Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the Infectious Diseases Society of America.
      ,
      • Oliveria C.
      • Nasr A.
      • Brindle M.
      • Wales P.W.
      Ethanol locks to prevent catheter- related bloodstream infections in parenteral nutrition: A meta-analysis.
      ,
      • Pitts S.
      • Bergamo D.
      • Cartaya C.
      • Gore B.
      Efficacy in the reduction of central line-associated bloodstream infection in a patient with intestinal failure: An ethanol lock pediatric case study.
      ,
      • Restrepo D.
      • Laconi N.S.
      • Alcantar N.A.
      • West L.A.
      • Buttice A.L.
      • Patel S.
      • Kayton M.L.
      Inhibition of heparin precipitation, bacterial growth, and fungal growth with a combined isopopanol-ethanol locking solution for vascular access devices.
      ,
      • Schoot R.A.
      • van Ommen C.H.
      • Stijnen T.
      • Tissing W.J.E.
      • Michiels E.
      • Abbink F.C.H.
      • van de Wetering M.D.
      Prevention of central venous catheter-associated bloodstream infections in paeditric oncology patients using 70% ethanol locks: A randomized controlled mutli-centre trial.
      ). In general, MRSA intravascular catheter-related bloodstream infection may be treated for as short as 2 weeks after the first negative blood culture result if fever and bacteremia resolve within 72 hours of treatment and the child does not have comorbid conditions like diabetes, immunosuppression, neutropenia, intravascular prosthetic material (e.g., artificial valve or pacemaker), evidence of endocarditis, or suppurative thrombophlebitis. Children with these complicating features, or more severe or persistent infections, may require 4 to 6 weeks of antibiotics (
      • Mermel L.A.
      • Allon M.
      • Bouza E.
      • Craven D.E.
      • Flynn P.
      • O'Grady N.P.
      • Warren D.K.
      Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the Infectious Diseases Society of America.
      ).
      Infective endocarditis is a serious infection involving the endocardium, or innermost layer of the heart (
      • Cabell C.H.
      • Abrutyn E.
      • Karchmer A.W.
      Bacterial endocarditis: the disease, treatment, and prevention.
      ). Treatment of MRSA endocarditis requires prolonged treatment, typically 6 weeks, with high doses of antibiotics to overcome the characteristically high bacterial inocula and biofilm formation that allows for slower bacterial growth and division, resulting in reduced antibiotic effectiveness (
      • Baltimore R.S.
      • Gewitz M.
      • Baddour L.M.
      • Beerman L.B.
      • Jackson M.
      • Lockhart P.B.
      • Willoughby Jr., R.
      Infective endocarditis in childhood: 2015 update.
      ).
      Vancomycin remains the preferred agent for management of MRSA bacteremia and endocarditis. Potential alternative options include daptomycin or ceftaroline. Clindamycin and linezolid should be avoided because they exert bacteriostatic effects against S. aureus, and bactericidal agents are generally preferred in this clinical situation (
      • Baltimore R.S.
      • Gewitz M.
      • Baddour L.M.
      • Beerman L.B.
      • Jackson M.
      • Lockhart P.B.
      • Willoughby Jr., R.
      Infective endocarditis in childhood: 2015 update.
      ,
      • Liu C.
      • Bayer A.
      • Cosgrove S.E.
      • Daum R.S.
      • Fridkin S.K.
      • Gorwitz R.J.
      • Chambers H.F.
      Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.
      ). When treating MRSA endocarditis for patients with prosthetic cardiac material, vancomycin should be combined with both gentamicin for synergistic bacterial killing and rifampin for enhanced biofilm penetration (
      • Baltimore R.S.
      • Gewitz M.
      • Baddour L.M.
      • Beerman L.B.
      • Jackson M.
      • Lockhart P.B.
      • Willoughby Jr., R.
      Infective endocarditis in childhood: 2015 update.
      ,
      • Hall Snyder A.D.
      • Vidaillac C.
      • Rose W.
      • McRoberts J.P.
      • Rybak M.J.
      Evaluation of high-dose daptomycin versus vancomycin alone or combined with clarithromycin or rifampin against Staphylococcus aureus and S. epidermidis in a novel in vitro PK/PD model of bacterial biofilm.
      ).

      Infections of the Central Nervous System

      Although MRSA is not a traditional meningitis pathogen, it commonly causes central nervous system (CNS) infections in association with trauma and neurosurgery (e.g., instrumentation for cerebrospinal fluid shunts). Vancomycin is the preferred treatment for MRSA CNS infections; alternative agents include linezolid or SMX-TMP (
      • Liu C.
      • Bayer A.
      • Cosgrove S.E.
      • Daum R.S.
      • Fridkin S.K.
      • Gorwitz R.J.
      • Chambers H.F.
      Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.
      ,
      • Tunkel A.R.
      • Hartman B.J.
      • Kaplan S.L.
      • Kaufman B.A.
      • Roos K.L.
      • Scheld W.M.
      • Whitley R.J.
      Practice guidelines for the management of bacterial meningitis.
      ). Rifampin is not added routinely but may be considered in selected situations, such as a slower than expected clinical or microbiological response or an inability to remove infected hardware (
      • Tunkel A.R.
      • Hartman B.J.
      • Kaplan S.L.
      • Kaufman B.A.
      • Roos K.L.
      • Scheld W.M.
      • Whitley R.J.
      Practice guidelines for the management of bacterial meningitis.
      ). Higher vancomycin doses and troughs are recommended for the management of CNS infections, and therapy generally lasts at least 2 weeks for meningitis but may be significantly longer, up to 6 weeks or more, for brain or spinal abscesses (
      • Liu C.
      • Bayer A.
      • Cosgrove S.E.
      • Daum R.S.
      • Fridkin S.K.
      • Gorwitz R.J.
      • Chambers H.F.
      Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.
      ). Duration of antibiotic treatment may also be prolonged in the setting of retained infected hardware or persistent clinical symptoms or positive culture results.

      Antimicrobial Agents

      Vancomycin

      Vancomycin, a glycopeptide antibiotic, exerts bactericidal effects on S. aureus by binding to the d-alanyl–d-alanine terminus of the peptidoglycan molecules that make up the bacterial cell wall. These subunits are then unavailable for cell wall incorporation, and synthesis is halted (
      Lexi-Comp, Inc
      Lexi-Drugs®.
      ,
      • Murray B.E.
      • Arias C.A.
      • Nannini E.C.
      Glycopeptides (vancomycin and teicoplanin), streptogramins (quinupristin-dalfopristin), lipopeptides (daptomycin), and lipoglycopeptides.
      ). Vancomycin has long been a drug of choice against MRSA and is included in national guidelines for serious MRSA infections of all body sites.
      The typical starting approach to vancomycin dosing in pediatric patients with normal renal function is the administration of a 15-mg/kg dose every 6 hours (
      Lexi-Comp, Inc
      Lexi-Drugs®.
      ,
      • Liu C.
      • Bayer A.
      • Cosgrove S.E.
      • Daum R.S.
      • Fridkin S.K.
      • Gorwitz R.J.
      • Chambers H.F.
      Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.
      ). To ensure clinical efficacy and safety, serum vancomycin concentrations are routinely monitored at the third dose. The pharmacodynamic parameter most closely associated with vancomycin efficacy is the ratio between the area under the concentration–time curve (AUC) and the vancomycin minimum inhibitory concentration (MIC). In adult patients, an AUC-to-MIC ratio of at least 400 has been correlated with successful treatment of MRSA bacteremia (
      • Kullar R.
      • Davis S.L.
      • Levine D.P.
      • Rybak M.J.
      Impact of vancomycin exposure on outcomes in patients with methicillin-resistant Staphylococcus aureus bacteremia: support for consensus guidelines suggested targets.
      ). Because this calculation is mathematically cumbersome to perform at the bedside, serum trough concentrations of vancomycin are often used as surrogate markers for AUC. When treating an infection caused by a MRSA isolate with a vancomycin MIC of 1 mg/L, serum trough concentrations between 15 and 20 mg/L correlate with an AUC-to-MIC ratio of 400 in adult patients (
      • Rybak M.
      • Lomaestro B.
      • Rotschafer J.C.
      • Moellering R.
      • Craig W.
      • Billeter M.
      • Levine D.P.
      Therapeutic monitoring of vancomycin in adult patients: A consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists.
      ). Pharmacokinetic modeling studies in children describe different relationships between trough concentrations and AUC-to-MIC ratios. The targeted AUC-to-MIC ratio of 400 or greater was achieved with attainment of vancomycin trough concentrations as low as 7 to 10 mg/L in modeling studies using pharmacokinetic parameters derived from pediatric patients (
      • Frymoyer A.
      • Guglielmo B.J.
      • Hersh A.L.
      Desired vancomycin trough serum concentration for treating invasive methicillin-resistant staphylococcal infections.
      ,
      • Le J.
      • Bradley J.S.
      • Murray W.
      • Romanowski G.L.
      • Tran T.T.
      • Nguyen N.
      • Capparelli E.V.
      Improved vancomycin dosing in children using area under the curve exposure.
      ).
      The maintenance of trough concentrations above a minimum of 10 mg/L is desirable to avoid the development of vancomycin resistance (
      • Howden B.P.
      • Ward P.B.
      • Charles P.G.
      • Korman T.M.
      • Fuller A.
      • dr Cros P.
      • Grayson M.L.
      Treatment outcomes for serious infections caused by methicillin-resistant Staphylococcus aureus with reduced vancomycin susceptibility.
      ,
      • Sakoulas G.
      • Gold H.S.
      • Cohen R.A.
      • Venkataraman L.
      • Moellering R.C.
      • Eliopoulos G.M.
      Effects of prolonged vancomycin administration on methicillin-resistant Staphylococcus aureus (MRSA) in a patient with recurrent bacteraemia.
      ). Ideal therapeutic drug monitoring targets for vancomycin in children continue to be an area of debate. Although institutional protocols vary, serum trough concentrations between 10 and 15 mg/L are generally targeted for superficial infections and troughs between 15 and 20 mg/L for more severe or invasive infections. Lower concentrations are usually targeted in neonates, depending on institutional practice and unique patient characteristics like gestational age, weight, renal function, and infection severity.
      Nephrotoxicity is a well-described adverse effect of vancomycin therapy, especially when used at high doses or in conjunction with other nephrotoxins. This risk is minimized when trough concentrations are kept below 20 mg/L (
      • Rybak M.
      • Lomaestro B.
      • Rotschafer J.C.
      • Moellering R.
      • Craig W.
      • Billeter M.
      • Levine D.P.
      Therapeutic monitoring of vancomycin in adult patients: A consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists.
      ). A common patient complaint is the development of flushing or tachycardia during vancomycin infusion, commonly referred to as “red man syndrome” (
      • Healy D.P.
      • Sahai J.V.
      • Fuller S.H.
      • Polk R.E.
      Vancomycin-induced histamine release and “red man syndrome”: Comparison of 1- and 2-hour infusions.
      ). This reaction is associated with histamine release and can be managed in most patients by slowing the rate of infusion or premedicating with an antihistaminergic agent such as diphenhydramine.

      Clindamycin

      Clindamycin is a lincosamide antibiotic that inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit (
      Lexi-Comp, Inc
      Lexi-Drugs®.
      ). As a protein synthesis inhibitor able to reduce toxin release, clindamycin is an important adjuvant therapy for toxin-mediated illnesses like staphylococcal TSS. Because it lacks bactericidal effects against MRSA, clindamycin is not recommended for use in patients with persistent bacteremia or endovascular infections, but it is commonly used for skin and bone infections (
      • Baltimore R.S.
      • Gewitz M.
      • Baddour L.M.
      • Beerman L.B.
      • Jackson M.
      • Lockhart P.B.
      • Willoughby Jr., R.
      Infective endocarditis in childhood: 2015 update.
      ). Clindamycin is also limited by its inability to cross the blood–brain barrier, negating its utility for CNS infections (
      Lexi-Comp, Inc
      Lexi-Drugs®.
      ).
      Clindamycin has high oral bioavailability and can be readily transitioned from the IV to oral route of administration. When studied in the setting of musculoskeletal infections including osteomyelitis, conversion to oral clindamycin yielded equivalent outcomes and eliminated risks associated with long-term IV therapy (
      • Erickson C.M.
      • Sue P.K.
      • Stewart K.
      • Thomas M.I.
      • Lindsay E.A.
      • Jo C.
      • Copley L.A.B.
      ,
      • Keren R.
      • Shah S.S.
      • Srivastava R.
      • Rangel S.
      • Bendel-Stenzel M.
      • Harik N.
      • Parker A.
      Comparative effectiveness of intravenous vs oral antibiotics for postdischarge treatment of acute osteomyelitis in children.
      ). Typical IV dosing for serious infections is a dose of 10 mg/kg every 6 hours, which is usually transitioned to 10 mg/kg orally every 8 hours (
      • Bradley J.S.
      • Byington C.L.
      • Shah S.S.
      • Alverson B.
      • Carter E.R.
      • Harrison C.
      • Swanson J.T.
      The management of community-acquired pneumonia in infants and children older than 3 months of age: Clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America.
      ,
      • Erickson C.M.
      • Sue P.K.
      • Stewart K.
      • Thomas M.I.
      • Lindsay E.A.
      • Jo C.
      • Copley L.A.B.
      ,
      Lexi-Comp, Inc
      Lexi-Drugs®.
      ). These two dosing schemes were deemed equally effective when compared for the management of musculoskeletal infections (
      • Erickson C.M.
      • Sue P.K.
      • Stewart K.
      • Thomas M.I.
      • Lindsay E.A.
      • Jo C.
      • Copley L.A.B.
      ). The most commonly reported adverse effect after clindamycin administration is gastrointestinal distress. Clindamycin commonly causes diarrhea and, as with all antibiotics, confers a risk for antibiotic-associated Clostridium difficile diarrhea.

      Linezolid

      Linezolid is an oxazolidinone antibiotic that inhibits bacterial protein synthesis by binding to the 50S subunit of the bacterial ribosome (
      • Cox H.L.
      • Donowitz G.R.
      Linezolid and other oxazolidinones.
      ). Linezolid is approved by the U.S. Food and Drug Administration (FDA) for use in adults and children of all ages for MRSA SSTIs and pneumonia (
      Pfizer, Inc
      Zyvox [package insert].
      ). Linezolid is not recommended for MRSA bacteremia or endocarditis because of its bacteriostatic effects and an observed mortality imbalance in a noninferiority study (
      • Wilcox M.H.
      • Tack K.J.
      • Herr D.J.
      • Ruf B.R.
      • Ijzerman M.M.
      • Croos-Dabrera R.V.
      • Knirsch C.
      Complicated skin and skin-structure infections and catheter-related bloodstream infections: Noninferiority of linezolid in a phase 3 study.
      ) comparing linezolid to vancomycin for catheter-related bloodstream infections. A 21.5% mortality rate was reported for patients who received linezolid, compared with 16% of patients who received vancomycin; however, it is noted that this imbalance appeared to have been driven by concomitant Gram-negative pathogens (
      • Liu C.
      • Bayer A.
      • Cosgrove S.E.
      • Daum R.S.
      • Fridkin S.K.
      • Gorwitz R.J.
      • Chambers H.F.
      Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.
      ,
      • Wilcox M.H.
      • Tack K.J.
      • Herr D.J.
      • Ruf B.R.
      • Ijzerman M.M.
      • Croos-Dabrera R.V.
      • Knirsch C.
      Complicated skin and skin-structure infections and catheter-related bloodstream infections: Noninferiority of linezolid in a phase 3 study.
      ). Adolescents may receive the adult dose of 600 mg every 12 hours, whereas doses of 10 mg/kg every 8 hours are recommended for younger patients (
      Pfizer, Inc
      Zyvox [package insert].
      ). Prolonged use of linezolid increases the incidence of drug-induced thrombocytopenia and other myelosuppressive effects, which generally normalize after stopping linezolid but must be considered, particularly in children who have blood dyscrasias at baseline (
      • Garazzino S.
      • Krzysztofiak A.
      • Esposito S.
      • Castagnola E.
      • Plebani A.
      • Galli L.
      • Tovo P.
      Use of linezolid in infants and children: a retrospective multicentre study of the Italian Society of Paediatric Infectious Diseases.
      ). Other adverse effects, including neuropathies and lactic acidosis, have been described. Linezolid is a monoamine oxidase inhibitor and thus should not be administered with foods rich in tyramine like smoked meats, red wine, or aged cheese. Additionally, concomitant administration of serotonin or norepinephrine reuptake inhibitors like citalopram or duloxetine can lead to neuroleptic malignant syndrome or serotonin syndrome (
      Pfizer, Inc
      Zyvox [package insert].
      ).

      Daptomycin

      Daptomycin is a lipopeptide antibiotic that exerts its bactericidal activity by inserting its lipophilic tail into membranes of Gram-positive pathogens, causing a loss of potassium ions with subsequent depolarization leading to cell death, among other losses to membrane viability (
      • Hobbs J.K.
      • Miller K.
      • O'Neill A.J.
      • Chopra I.
      Consequences of daptomycin-mediated membrane damage in Staphylococcus aureus.
      ,
      • Jung D.
      • Rozek A.
      • Okon M.
      • Hancock R.E.W.
      Structural transitions as determinants of the action of the calcium-dependent antibiotic daptomycin.
      ). Given its broader Gram-positive spectrum activity, higher cost, and FDA approval for use in adults only, daptomycin is typically reserved for second-line treatment of MRSA bacteremia, usually in the setting of vancomycin failure or intolerance. Additionally, there is an increasing role for daptomycin in the management of bacteremia cause by strains of MRSA with vancomycin MICs greater than 1 mg/L, with evidence suggesting improved clinical outcomes with daptomycin over vancomycin in adult patients (
      • Moore C.L.
      • Osaki-Kyan P.
      • Haque N.Z.
      • Perri M.
      • Donabedian S.
      • Zervos M.J.
      Daptomycin versus vancomycin for bloodstream infections due to methicillin-resistant Staphylococcus aureus with a high vancomycin minimum inhibitory concentration: A case-control study.
      ,
      • Murray K.P.
      • Zhao J.
      • Davis S.L.
      • Kullar R.
      • Kaye K.
      • Lephart P.
      • Rybak M.J.
      Early use of daptomycin versus vancomycin for methicillin-resistant Staphylococcus aureus bacteremia with vancomycin MIC > 1 mg/L: A matched cohort study.
      ). Although the manufacturer recommends daptomycin dosing for the treatment of S. aureus bacteremia in adult patients of 6 mg/kg once daily, many clinicians use higher doses, up to 8 mg/kg or greater, particularly in the setting of concomitant endocarditis (
      • Kullar R.
      • Davis S.L.
      • Levine D.P.
      • Zhao J.J.
      • Crank C.W.
      • Segreti J.
      • Rybak M.J.
      High-dose daptomycin for treatment of complicated gram-positive infections: a large, multicenter, retrospective study.
      ). Daptomycin is not currently approved for use in children. Pharmacokinetic data indicate more rapid daptomycin clearance and overall reduced drug exposure among younger children compared with adolescents and adults; alternative doses of daptomycin have been investigated in some small pediatric studies. Available evidence suggests daily doses of 8- to 10-mg/kg yield serum concentrations, similar to those attained by a 4- to 6-mg/kg dose in adults (
      • Abdel-Rahman S.M.
      • Benziger D.P.
      • Jacobs R.F.
      • Jafri H.S.
      • Fischer Hong E.
      • Kearns G.L.
      Single-dose pharmacokinetics of daptomycin in children with suspected or proved gram-positive infections.
      ,
      • Abdel-Rahman S.M.
      • Chandorkar G.
      • Akins R.L.
      • Bradley J.S.
      • Jacobs R.F.
      • Donovan J.
      • Benziger D.P.
      Single-dose pharmacokinetics and tolerability of daptomycin 8 to 10 mg/kg in children aged 2 to 6 years with suspected or proved gram-positive infections.
      ,
      • Antachopoulos C.
      • Iosifidis E.
      • Sarafidis K.
      • Bazoti F.
      • Gikas E.
      • Katragkou A.
      • Roilides E.
      Serum levels of daptomycin in pediatric patients.
      ). Daptomycin is currently being studied for the treatment of children with AHO in children ages 1 to 7 years receiving daily doses of 12 mg/kg, children between the ages of 7 and 12 years receiving 9 mg/kg, and children ages 12 years and older receiving 7 mg/kg (
      Cubist Pharmaceuticals LLC
      Safety and efficacy study of Daptomycin compared to active comparator in pediatric participants with acute hematogenous osteomyelitis.
      ). Because of nervous system and/or muscular system adverse effects, the package insert warns against use in patients younger than 12 months (
      Merck & Co., Inc
      Cubicin [package insert].
      ).

      Ceftaroline

      Ceftaroline is a novel advanced-generation cephalosporin, and it is the first β-lactam with activity against MRSA. Ceftaroline inhibits bacterial cell wall synthesis by binding to a transpeptidase enzyme involved in cell wall formation, even in the presence of mutations rendering other β-lactams ineffective (
      • Kosowka-Shick K.
      • McGhee P.L.
      • Appelbaum P.C.
      Affinity of ceftaroline and other β-lactams for penicillin-binding proteins from Staphylococcus aureus and Streptococcus pneumoniae.
      ). Ceftaroline was approved for use in adults by the FDA in 2010 for the treatment of acute bacterial skin and skin structure infections (ABSSIs) and CAP for children ages 2 months and older (
      Allergan, Inc
      Teflaro [package insert].
      ). Although ceftaroline was studied and approved for acute bacterial skin and skin structure infections caused by MRSA, its use in pneumonia was approved only for methicillin-susceptible S. aureus, Streptococcus pneumoniae, Haemophilus influenzae, Escherichia coli, and Klebsiella species (
      Allergan, Inc
      Teflaro [package insert].
      ,
      • Cannavino C.R.
      • Nemeth A.
      • Korczowski B.
      • Bradley J.S.
      • O'Neal T.
      • Jandourek A.
      • Kaplan S.L.
      A randomized, prospective study of pediatric patients with community-acquired pneumonia treated with ceftaroline versus ceftriaxone.
      ,
      • Korczowski B.
      • Antadze T.
      • Giorgobiani M.
      • Stryjewski M.E.
      • Jandourek A.
      • Smith A.
      • Bradley J.S.
      A multicenter, randomized, observer-blinded, active-controlled study to evaluate the safety and efficacy of ceftaroline versus comparator in pediatric patients with acute bacterial skin and skin structure infection.
      ). Table 1 summarizes approved dosing specific to MRSA skin infections. Higher doses have been reported for both children and adults with invasive infections. Successful treatment of complicated MRSA bacteremia, including endocarditis with a dose of 600 mg every 8 hours instead of the FDA-approved 600 mg every 12 hours, has been reported in adult patients (
      • Ho T.T.
      • Cadena J.
      • Childs L.M.
      • Gonzalez-Velez M.
      • Lewis II, J.S.
      Methicillin-resistant Staphylococcus aureus bacteremia and endocarditis treated with ceftaroline salvage therapy.
      ). Additionally, off-label use of ceftaroline for MRSA respiratory infections has been described in children with cystic fibrosis (
      • Cannavino C.R.
      • Mendes R.E.
      • Sader H.S.
      • Farrell D.J.
      • Critchley I.A.
      • Biek D.
      • Bradley J.S.
      Evolution of ceftaroline-resistant MRSA in a child with cystic fibrosis following repeated antibiotic exposure.
      ,
      • Molloy L.
      • Snyder A.H.
      • Srivastava R.
      • Rybak M.J.
      • McGrath E.
      Ceftaroline fosamil for methicillin-resistant Staphylococcus aureus pulmonary exacerbation in a pediatric cystic fibrosis patient.
      ,
      • Zobell J.T.
      • Epps K.L.
      • Young D.C.
      • Montague M.
      • Olson J.
      • Ampofo K.
      • Dasenbrook E.
      Utilization of antibiotics for methicillin-resistant Staphylococcus aureus infection in cystic fibrosis.
      ), although resistance has been described, and optimal dosing remains unknown. In addition to MRSA and other Gram-positive organisms, ceftaroline is also active against a variety of Gram-negative pathogens including most Enterobacteriaceae as noted earlier (
      Allergan, Inc
      Teflaro [package insert].
      ). Although this may be advantageous for patients with concomitant MRSA and Gram-negative infections, good antimicrobial stewardship involves the use of the narrowest spectrum agents possible, and ceftaroline has a broader spectrum of Gram-negative activity than do most other MRSA treatment options.
      Table 1Recommended pediatric doses of anti-staphylococcal antibiotics
      DrugDose (mg/kg/day unless otherwise specified)Common adverse effectsMonitoring parameters
      Clindamycin, intravenous40 divided every 6 hours

      Maximum = dose of 600–900 mg
      Diarrhea including Clostridium difficile colitis, hepatotoxicityStool output if warranted, LFTs
      Clindamycin, oral30 divided every 8 hours

      Maximum = dose of 450–600 mg
      Vancomycin, intravenous60 divided every 6–8 hours

      Adjust per targeted serum trough concentration

      Empiric dose may be altered based on severity of illness and baseline renal function
      Nephrotoxicity, infusion-related reactions, ototoxicity, neutropeniaBUN, SCr, urine output, serum vancomycin concentrations, CBC
      Linezolid, intravenous or oralUnder 12 years old: 30 divided every 8 hours; maximum = dose of 600 mg

      12 years of age and older: 600 mg every 12 hours
      Thrombocytopenia, hepatotoxicity, peripheral neuropathy, optic neuritis, serotonin syndrome with concomitant serotonergic agentsCBC, LFTs, interacting foods or medications
      Daptomycin, intravenous6–10 once dailyRhabdomyolysis, hepatotoxicityCPK, BUN, SCr, LFTs
      SMX-TMP, intravenous or oral8–12 (TMP component) divided every 12 hours

      Consider higher doses (10–20) for CNS infections
      Elevated SCr, myelosuppression, hepatotoxicityBUN, SCr

      CBC, LFTs
      Ceftaroline
      Doses for U.S. Food and Drug Administration–approved indications only. Alternative doses have been reported for different infections; see text.
      , intravenous
      2 months to <2 years old: 24 divided every 8 hours

      2 to <18 years weighing ≤33 kg: 36 divided every 8 hours

      2 to <18 years weighing >33 kg: 400 mg every 8 hours or 600 mg every 12 hours
      Seroconversion to positive direct Coombs test results, neutropeniaBUN, SCr

      CBC
      Gentamicin, intravenous3–6 divided every 8 hours

      Adjust per targeted serum peak (3–4 mg/L) and trough (<1 mg/L) concentrations
      Nephrotoxicity, ototoxicityBUN, SCr, urine output, serum gentamicin concentrations
      Rifampin, intravenous or oral20 divided every 8 hoursRed/orange discoloration of body fluids, hepatotoxicityLFTs, CBC
      Note. BUN, blood urea nitrogen; CBC, complete blood count; CNS, central nervous system; CPK, creatine phosphokinase; LFTs, liver function tests; SCr, serum creatinine; SMX-TMP, sulfamethoxazole/trimethoprim; TMP, trimethoprim.
      a Doses for U.S. Food and Drug Administration–approved indications only. Alternative doses have been reported for different infections; see text.

      Adjunctive and Alternative Antibiotics

      Gentamicin and rifampin have infrequent but important roles in the management of selected MRSA infections. Gentamicin is an aminoglycoside that inhibits bacterial protein synthesis by binding to bacterial ribosomes (
      • Leggett J.E.
      Aminoglycosides.
      ). For the treatment of MRSA endocarditis in the setting of a prosthetic valve, gentamicin is routinely added with rifampin to the primary cell wall active agent, typically vancomycin, for the first 2 weeks of treatment only. The most recent consensus guideline for pediatric endocarditis also provides the option of adding gentamicin for the first 3 to 5 days of treatment for native valve endocarditis, a suggestion extrapolated from in vitro modeling (
      • Baltimore R.S.
      • Gewitz M.
      • Baddour L.M.
      • Beerman L.B.
      • Jackson M.
      • Lockhart P.B.
      • Willoughby Jr., R.
      Infective endocarditis in childhood: 2015 update.
      ). The role of aminoglycosides in native valve endocarditis has been studied in adult patients and identified increased nephrotoxicity with no added clinical benefit (
      • Cosgrove S.E.
      • Vigliani G.A.
      • Campion M.
      • Fowler Jr., V.G.
      • Abrutyn E.
      • Corey G.R.
      • Boucher H.W.
      Initial low-dose gentamicin for Staphylococcus aureus bacteremia and endocarditis is nephrotoxic.
      ). Although the use of additional gentamicin in native valve endocarditis has not been studied in children, similar results of increased kidney injury without improved clinical outcomes have been reported in the settings of both Gram-negative and enterococcal bacteremia (
      • Ibrahim S.L.
      • Zhang L.
      • Brady T.M.
      • Hsu A.J.
      • Cosgrove S.E.
      • Tamma P.D.
      Low-dose gentamicin for uncomplicated Enterococcus faecalis bacteremia may be nephrotoxic in children.
      ,
      • Tamma P.D.
      • Turnbull A.E.
      • Harris A.D.
      • Milstone A.M.
      • Hsu A.J.
      • Cosgrove S.E.
      Less is more: Combination antibiotic therapy for the treatment of gram-negative bacteremia in pediatric patients.
      ). Traditional synergy dosing as recommended by consensus guidelines is presented in Table 1, but once-daily dosing has been recommended by others (
      • Nichols K.R.
      • Israel E.N.
      • Thomas C.A.
      • Knoderer C.A.
      Optimizing guideline-recommended antibiotic doses for pediatric infective endocarditis.
      ).
      In addition to prosthetic valve endocarditis, rifampin may also be considered for adjuvant therapy for CNS infections or potentially for selected bone and joint infections. Rifampin is a protein synthesis inhibitor, and its primary advantage for these selected infections is its excellent penetration through biofilms and also into the CNS. Resistance is known to develop rapidly when rifampin is used alone, so it must always be used in combination with another antibiotic (
      • Liu C.
      • Bayer A.
      • Cosgrove S.E.
      • Daum R.S.
      • Fridkin S.K.
      • Gorwitz R.J.
      • Chambers H.F.
      Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.
      ).
      Dosing recommendations vary, but the typical treatment dose is 20 mg/kg/day divided in two or three doses. Rifampin is available for IV or oral administration and has good oral bioavailability, allowing for IV-to-oral conversion without any dose changes. Rifampin can cause hepatotoxicity, and patients and parents must be counseled about its benign, but potentially alarming, adverse effect of turning body fluids like urine and tears a red–orange color. Finally, rifampin is a potent inducer of cytochrome P450 enzymes, which results in enhanced metabolism, and subsequently reduced concentrations, of the many drugs dependent on these enzymes for metabolism. Some common examples of affected medications include tacrolimus, amiodarone, prednisone, and azole antifungals.
      The tetracycline antibiotics (tetracycline, doxycycline, minocycline) are alternative agents for the outpatient management of SSTIs. These agents also interfere with bacterial protein synthesis and are bacteriostatic; they are typically reserved as alternative treatment options for MRSA SSTIs and are not used in invasive infections (
      • Liu C.
      • Bayer A.
      • Cosgrove S.E.
      • Daum R.S.
      • Fridkin S.K.
      • Gorwitz R.J.
      • Chambers H.F.
      Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.
      ,
      • Moffa M.
      • Brook I.
      Tetracyclines, glycylcyclines, and chloramphenicol.
      ). Important adverse effects include photosensitivity and esophagitis, and these agents should be avoided for treating MRSA infections in patients younger than 8 years because they cause irreversible tooth discoloration when used during tooth development, although this is more common with long-term therapy and does not preclude use for rickettsial infections (
      Lexi-Comp, Inc
      Lexi-Drugs®.
      ,
      • Todd S.R.
      • Dahlgreen F.S.
      • Traeger M.S.
      • Beltran-Aguilar E.D.
      • Marianos D.W.
      • Hamilton C.
      • Regan J.J.
      No visible dental staining in children treated with doxycycline for suspected Rocky Mountain spotted fever.
      ).

      Mechanisms of Antimicrobial Resistance

      Antimicrobial resistance of S. aureus to a variety of agents has been described. The most common mechanisms are summarized in Table 2 and described in detail below.
      Table 2Common mechanisms of antibiotic resistance in S. aureus
      Mechanism of resistanceDrug class
      β-lactamasesNatural penicillins
      Aminopenicillins
      Penicillin-binding protein alterationsPenicillinase-resistant penicillins
      Cephalosporins
      Except ceftaroline.
      β-lactam–β-lactamase inhibitor combinations
      Peptidoglycan overproductionVancomycin
      Daptomycin
      Altered glycopeptide precursorsVancomycin
      Ribosomal binding site methylationClindamycin
      Macrolides
      a Except ceftaroline.

      Resistance to Methicillin

      The activity of β-lactams against S. aureus relies on their structural similarity to the d-alanyl–d-alanine portion of the peptidoglycan subunits of the bacterial cell wall. During cell wall formation, the bacterial enzyme transpeptidase crosslinks d-alanyl–d-alanine terminals together (
      • Berger-Bachi B.
      • Rohrer S.
      Factors influencing methicillin resistance in Staphylococci.
      ,
      • Doi Y.
      • Chambers H.F.
      Penicillins and β-lactamase inhibitors.
      ). In the setting of methicillin-susceptible S. aureus, the bacterial transpeptidase is unable to discern between d-alanyl–d-alanine and the β-lactam ring, and it errantly binds to the β-lactam antibiotic, which halts bacterial cell wall production. Because it attaches to the β-lactam ring, the bacterial transpeptidase enzyme is also referred to as penicillin-binding protein (PBP).
      S. aureus infections were historically uniformly susceptible to penicillin until the identification of a penicillinase enzyme produced by S. aureus capable of hydrolyzing and thus inactivating penicillin, as well as the aminopenicillins amoxicillin and ampicillin. By the 1960s, this penicillinase was nearly uniformly present in all S. aureus strains (
      • Chambers H.F.
      • DeLeo F.R.
      Waves of resistance: Staphylococcus aureus in the antibiotic era.
      ). Because the penicillinase enzyme is narrow in its ability to hydrolyze β-lactam rings, it cannot inactivate penicillinase-resistant penicillins like methicillin, β-lactam/β-lactamase inhibitor combinations like ampicillin/sulbactam, piperacillin/tazobactam, or cephalosporins. Thus, these agents remained active against S. aureus even in the presence of penicillinase.
      Although penicillinase results in destruction of certain antibiotics (natural and aminopenicillins), methicillin resistance is conferred by alteration of the drug target without destruction of antibiotics. In MRSA, the bacterial transpeptidase enzyme, or PBP, is mutated to PBP-2a, which has low affinity for the β-lactam ring and is therefore able to continue incorporating d-alanyl-d-alanine subunits into the bacterial cell wall without binding to the β-lactam antibiotic (
      • Berger-Bachi B.
      • Rohrer S.
      Factors influencing methicillin resistance in Staphylococci.
      ;
      • Chambers H.F.
      • DeLeo F.R.
      Waves of resistance: Staphylococcus aureus in the antibiotic era.
      ). The PBP-2a mutation is encoded by the mecA gene, which is found within the mobile genetic element staphylococcal cassette chromosome mec, or SCCmec (
      • Hiramatsu K.
      • Cui L.
      • Kuroda M.
      • Ito T.
      The emergence and evolution of methicillin-resistant Staphylococcus aureus.
      ). Importantly, as a mobile element, mecA can be acquired by horizontal gene transfer, promoting the spread of methicillin resistance (
      • Chambers H.F.
      • DeLeo F.R.
      Waves of resistance: Staphylococcus aureus in the antibiotic era.
      ).

      Resistance to Vancomycin

      Vancomycin resistance among MRSA remains rare, but it can be difficult to detect and can lead to treatment failure. Vancomycin-intermediate S. aureus (VISA) can develop after prolonged, and particularly subtherapeutic, exposure to vancomycin (
      • Howden B.P.
      • Ward P.B.
      • Charles P.G.
      • Korman T.M.
      • Fuller A.
      • dr Cros P.
      • Grayson M.L.
      Treatment outcomes for serious infections caused by methicillin-resistant Staphylococcus aureus with reduced vancomycin susceptibility.
      ). When vancomycin is present for long enough at inadequate serum concentrations, S. aureus can adapt to become less susceptible by developing a thickened cell wall, requiring a higher concentration of vancomycin to bind to the greater number of cell wall precursors (
      • Ciu L.
      • Ma X.
      • Sato K.
      • Okuma K.
      • Tenover F.C.
      • Mamizuka E.M.
      • Hiramatsu K.
      Cell wall thickening is a common feature of vancomycin resistance in Staphylococcus aureus.
      ). Additionally, VISA may have a slower rate of growth and reproduction, offering fewer opportunities for vancomycin to interrupt cell wall synthesis (
      • Pfeltz R.F.
      • Singh V.K.
      • Schmidt J.L.
      • Batter M.A.
      • Baranyk C.S.
      • Nadakavukaren M.J.
      • Wilkinson B.J.
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      ). Although VISA may be identified by MICs between 4 and 8 μg/ml, heterogeneous VISA (hVISA) is harder to detect and also presents the risk of vancomycin failure (
      • Casapao A.M.
      • Leonard S.N.
      • Davis S.L.
      • Lodise T.P.
      • Patel N.
      • Goff D.A.
      • Rybak M.J.
      Clinical outcomes in patients with heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) bloodstream infection.
      ). Infections caused by hVISA consist of a small subpopulation of microorganisms with reduced vancomycin susceptibility among a much larger population of species fully susceptible to vancomycin (i.e., MIC ≤ 2 μg/ml). When the sample is tested for vancomycin susceptibility, the small subpopulation with reduced susceptibility is not detected, and the entire sample is interpreted as being fully susceptible to vancomycin. However, treatment with vancomycin in this scenario can lead to failure, persistence, and recurrence of infection (
      • Casapao A.M.
      • Leonard S.N.
      • Davis S.L.
      • Lodise T.P.
      • Patel N.
      • Goff D.A.
      • Rybak M.J.
      Clinical outcomes in patients with heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) bloodstream infection.
      ,
      • Gomes D.M.
      • Ward K.E.
      • LaPlante K.L.
      Clinical implications of vancomycin heteroresistant and intermediately susceptible Staphylococcus aureus.
      ). In contrast to VISA, wherein the cell wall is thicker but its components are otherwise unchanged, the cell wall subunits of vancomycin-resistant S. aureus terminate in a d-alanine–d-lactate sequence instead of d-alanyl–d-alanine (
      • Gardete S.
      • Tomasz A.
      Mechanisms of vancomycin resistance in Staphylococcus aureus.
      ). Vancomycin has substantially less affinity and subsequent ability to bind to d-alanine–d-lactate, and is thus no longer effective.
      Vancomycin resistance among MRSA remains rare, but it can be difficult to detect and can lead to treatment failure.

      Resistance to Other Antibiotics

      Because clindamycin is widely used for the management of MRSA infections in children, understanding mechanisms and implications of resistance is important. Clindamycin resistance in S. aureus may be either constitutive or inducible, both of which involve the macrolide, lincosamide, streptogramin phenotype encoded by the erm gene. The macrolide, lincosamide, streptogramin phenotype promotes methylation of the bacterial ribosome, causing decreased antibiotic binding and ultimately resistance across the three classes of antibiotics (
      • Sasirekha B.
      • Usha M.S.
      • Amruta J.A.
      • Ankit S.
      • Brinda N.
      • Divya R.
      Incidence of constitutive and inducible clindamycin resistance among hospital-associated Staphylococcus aureus.
      ). Inducible resistance is identified by a positive double disk diffusion test result, confirmed by a blunted zone of bacterial clearance around a clindamycin disc in close proximity to an erythromycin disc (
      • Gardiner B.J.
      • Grayson M.L.
      • Wood G.M.
      Inducible resistance to clindamycin in Staphylococcus aureus: validation of Vitek-2 against CLSI D-test.
      ). Other mechanisms of resistance to a variety of antibiotics have been described. Reduced susceptibility to daptomycin is most widely observed among hVISA and VISA, likely because of the thickened cell wall hindering adequate penetration of daptomycin (
      • Ciu L.
      • Tominaga E.
      • Neoh H.
      • Hiramatsu K.
      Correlation between reduced daptomycin susceptibility and vancomycin resistance in vancomycin-intermediate Staphylococcus aureus.
      ,
      • Kelley P.G.
      • Gao W.
      • Ward P.B.
      • Howden B.P.
      Daptomycin non- susceptibility in vancomycin-intermediate Staphylococcus aureus (VISA) and heterogeneous-VISA (hVISA): implications for therapy after vancomycin treatment failure.
      ). Development of resistance to both linezolid and ceftaroline has been identified among patients with cystic fibrosis via the development of various mutations, attributed to subtherapeutic drug concentrations (
      • Cannavino C.R.
      • Mendes R.E.
      • Sader H.S.
      • Farrell D.J.
      • Critchley I.A.
      • Biek D.
      • Bradley J.S.
      Evolution of ceftaroline-resistant MRSA in a child with cystic fibrosis following repeated antibiotic exposure.
      ,
      • Gales A.C.
      • Sader H.S.
      • Andrade S.S.
      • Lutz L.
      • Machado A.
      • Barth A.L.
      Emergence of linezolid-resistant Staphylococcus aureus during treatment of pulmonary infection in a patient with cystic fibrosis.
      ,
      • Hill R.L.R.
      • Kearns A.M.
      • Nash J.
      • North S.E.
      • Pike R.
      • Newson T.
      • Livermore D.M.
      Linezolid-resistant ST36 methicillin-resistant Staphylococcus aureus association with prolonged linezolid treatment in two paediatric cystic fibrosis patients.
      ).

      Conclusion

      Infections caused by MRSA are common both in the community and hospital settings and represent a significant health care burden. Management of these disease states in children is further complicated by unique dosage requirements, adverse drug effects, and pharmacokinetic profiles. Clinicians must maintain a current, working knowledge of pharmacotherapy of these common infections that vary widely in terms of presentation and severity.

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      Biography

      Leah Molloy, Clinical Pharmacist Specialist, Infectious Diseases, Department of Pharmacy, Children's Hospital of Michigan, Detroit Medical Center, Detroit, MI.

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