Methicillin-Resistant Staphylococcus aureus: A Pharmacotherapy Primer

Abstract

Objectives1.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. 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 et al., 2011Liu 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.Clinical Infectious Diseases. 2011; 53: e18-e55Crossref Scopus (1896) Google Scholar, Lowy, 1998Lowy F.D. Staphylococcus aureus infections.The New England Journal of Medicine. 1998; 339: 520-532Crossref PubMed Scopus (4617) Google Scholar). 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. 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 and Moreillon, 2015Que Y. Moreillon P. Staphylococcus aureus (including staphylococcal toxic shock).in: Mandell G.L. Bennett J.E. Dolin R. Mandell, Douglas, and Bennett's principles and practice of infectious diseases. Saunders, Elsevier Inc, Philadelphia, PA2015Google Scholar). 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 and Moreillon, 2015Que Y. Moreillon P. Staphylococcus aureus (including staphylococcal toxic shock).in: Mandell G.L. Bennett J.E. Dolin R. Mandell, Douglas, and Bennett's principles and practice of infectious diseases. Saunders, Elsevier Inc, Philadelphia, PA2015Google Scholar, Rupp and Fey, 2015Rupp M.E. Fey P.D. Staphylococcus epidermidis and other coagulase- negative staphylococci.in: Mandell G.L. Bennett J.E. Dolin R. Mandell, Douglas, and Bennett's principles and practice of infectious diseases. Saunders, Elsevier Inc, Philadelphia, PA2015: 2272-2282Google Scholar). 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 and DeLeo, 2009Chambers H.F. DeLeo F.R. Waves of resistance: Staphylococcus aureus in the antibiotic era.Nature Reviews Microbiology. 2009; 7: 629-641Crossref PubMed Scopus (1725) Google Scholar). 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 and Moreillon, 2015Que Y. Moreillon P. Staphylococcus aureus (including staphylococcal toxic shock).in: Mandell G.L. Bennett J.E. Dolin R. Mandell, Douglas, and Bennett's principles and practice of infectious diseases. Saunders, Elsevier Inc, Philadelphia, PA2015Google Scholar). 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 and DeLeo, 2009Chambers H.F. DeLeo F.R. Waves of resistance: Staphylococcus aureus in the antibiotic era.Nature Reviews Microbiology. 2009; 7: 629-641Crossref PubMed Scopus (1725) Google Scholar, Que and Moreillon, 2015Que Y. Moreillon P. Staphylococcus aureus (including staphylococcal toxic shock).in: Mandell G.L. Bennett J.E. Dolin R. Mandell, Douglas, and Bennett's principles and practice of infectious diseases. Saunders, Elsevier Inc, Philadelphia, PA2015Google Scholar). 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 and DeLeo, 2009Chambers H.F. DeLeo F.R. Waves of resistance: Staphylococcus aureus in the antibiotic era.Nature Reviews Microbiology. 2009; 7: 629-641Crossref PubMed Scopus (1725) Google Scholar, Iwamoto et al., 2013Iwamoto M. Mu Y. Lynfield R. Bulens S.N. Nadle J. Aragon D. Lessa F.C. Trends in invasive methicillin-resistant Staphylococcus aureus infections.Pediatrics. 2013; 132: e817-e824Crossref PubMed Scopus (92) Google Scholar). MRSA continues to represent a significant health care challenge today. 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…Box 1Antibiotic options for selected MRSA infectionsSkin and skin structure infections•Clindamycin•SMX-TMP•Vancomycin•Linezolid•Ceftarolinea•Daptomycinb•DoxycyclinecOsteomyelitis•Clindamycin•Vancomycin•Daptomycinb•LinezolidPneumonia•Vancomycin•Linezolid•Clindamycin•CeftarolineaCNS infection•Vancomycin•Linezolid•SMX-TMPBacteremia and infective endocarditis (IE)•Vancomycin (+rifampin + gentamicin for prosthetic valve IE)•Daptomycinb•CeftarolineaNote. 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. When managing bacteremia, a positive blood culture result alone is insufficient to guide antibiotic selection… Skin and skin structure infections•Clindamycin•SMX-TMP•Vancomycin•Linezolid•Ceftarolinea•Daptomycinb•DoxycyclinecOsteomyelitis•Clindamycin•Vancomycin•Daptomycinb•LinezolidPneumonia•Vancomycin•Linezolid•Clindamycin•CeftarolineaCNS infection•Vancomycin•Linezolid•SMX-TMPBacteremia 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. 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 et al., 2014Stevens 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.Clinical Infectious Diseases. 2014; 59: e10-e52Crossref PubMed Scopus (998) Google Scholar). 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 et al., 2011Liu 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.Clinical Infectious Diseases. 2011; 53: e18-e55Crossref Scopus (1896) Google Scholar). 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 (Kimberlin et al., 2015Kimberlin D.W. Brady M.T. Jackson M.A. Long S.S. Staphylococcal infections. American Academy of Pediatrics, Elk Grove Village, IL2015Google Scholar). 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 (Kimberlin et al., 2015Kimberlin D.W. Brady M.T. Jackson M.A. Long S.S. Staphylococcal infections. American Academy of Pediatrics, Elk Grove Village, IL2015Google Scholar). 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 et al., 2015Creech C.B. Al-Zubeidi D.N. Fritz S.A. Prevention of recurrent staphylococcal skin infections.Infectious Disease Clinics of North America. 2015; 29: 429-464Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar). This practice is referred to as decolonization, and it most often involves topical antimicrobial therapy including intranasal mupirocin and chlorhexidine washes (Stevens et al., 2014Stevens 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.Clinical Infectious Diseases. 2014; 59: e10-e52Crossref PubMed Scopus (998) Google Scholar). 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 et al., 2007Ellis M.W. Griffith M.E. Dooley D.P. McLean J.C. Jorgensen J.H. Patterson J.E. Hospenthal D.R. 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Mupirocin resistance in Staphylococcus aureus causing recurrent skin and soft tissue infections in children.Antimicrobial Agents and Chemotherapy. 2011; 55: 2431-2433Crossref PubMed Scopus (48) Google Scholar, McNeil et al., 2013McNeil 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.Pediatric Infectious Diseases Journal. 2013; 32: 124-128Crossref PubMed Scopus (46) Google Scholar) but was not confirmed in a recent randomized controlled trial (Hayden et al., 2016Hayden 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.Journal of Clinical Microbiology. 2016; 54: 2735-2742Crossref PubMed Scopus (50) Google Scholar). 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 et al., 2015Creech C.B. Al-Zubeidi D.N. Fritz S.A. Prevention of recurrent staphylococcal skin infections.Infectious Disease Clinics of North America. 2015; 29: 429-464Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, Liu et al., 2011Liu 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.Clinical Infectious Diseases. 2011; 53: e18-e55Crossref Scopus (1896) Google Scholar, Stevens et al., 2014Stevens 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.Clinical Infectious Diseases. 2014; 59: e10-e52Crossref PubMed Scopus (998) Google Scholar). 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 et al., 2016Self 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.Clinical Infectious Diseases. 2016; 63: 300-309Crossref PubMed Scopus (103) Google Scholar). 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 et al., 2011Liu 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.Clinical Infectious Diseases. 2011; 53: e18-e55Crossref Scopus (1896) Google Scholar, Self et al., 2016Self 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.Clinical Infectious Diseases. 2016; 63: 300-309Crossref PubMed Scopus (103) Google Scholar). 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 et al., 2016Kalil 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.Clinical Infectious Diseases. 2016; 63: e61-e111Crossref PubMed Scopus (1707) Google Scholar). Daptomycin serves no role in the management of pneumonia because it is inactivated by pulmonary surfactant (Merck & Co., Inc, 2015Merck & Co., IncCubicin [package insert]. Author, Whitehouse Station, NJ2015Google Scholar). 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. 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, 2012Gutierrez K. Osteomyelitis.in: Long S.S. Pickering L.K. Prober C.G. Principles and practice of pediatric infectious diseases. Elsevier Inc, Philadelphia, PA2012: 469-477Google Scholar). 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 et al., 2016Erickson C.M. Sue P.K. Stewart K. Thomas M.I. Lindsay E.A. Jo C. Copley L.A.B. Pediatric Infectious Diseases Journal. 2016; 35: 1092-1096Crossref PubMed Scopus (5) Google Scholar, Keren et al., 2015Keren 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.The Journal of the American Medical Association Pediatrics. 2015; 162: 120-128Google Scholar, Liu et al., 2011Liu 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.Clinical Infectious Diseases. 2011; 53: e18-e55Crossref Scopus (1896) Google Scholar). These prolonged durations of therapy may require long-term intravenous (IV) antibiotics, but equivalent outcomes have been observed after oral treatment with clindamycin (Erickson et al., 2016Erickson C.M. Sue P.K. Stewart K. Thomas M.I. Lindsay E.A. Jo C. Copley L.A.B. Pediatric Infectious Diseases Journal. 2016; 35: 1092-1096Crossref PubMed Scopus (5) Google Scholar, Keren et al., 2015Keren 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.The Journal of the American Medical Association Pediatrics. 2015; 162: 120-128Google Scholar) without the inconvenience or associated risks of IV treatment like thrombosis or infection. 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 et al., 2009Mermel 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.Clinical Infectious Diseases. 2009; 49: 1-45Crossref PubMed Scopus (2342) Google Scholar, Oliveria et al., 2012Oliveria C. Nasr A. Brindle M. Wales P.W. 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Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the Infectious Diseases Society of America.Clinical Infectious Diseases. 2009; 49: 1-45Crossref PubMed Scopus (2342) Google Scholar). Infective endocarditis is a serious infection involving the endocardium, or innermost layer of the heart (Cabell et al., 2003Cabell C.H. Abrutyn E. Karchmer A.W. Bacterial endocarditis: the disease, treatment, and prevention.Circulation. 2003; 107: e185-e187PubMed Google Scholar). 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 et al., 2015Baltimore R.S. Gewitz M. Baddour L.M. Beerman L.B. Jackson M. Lockhart P.B. Willoughby Jr., R. Infective endocarditis in childhood: 2015 update.Circulation. 2015; 132: 1487-1515Crossref PubMed Scopus (186) Google Scholar). 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 et al., 2015Baltimore R.S. Gewitz M. Baddour L.M. Beerman L.B. Jackson M. Lockhart P.B. Willoughby Jr., R. Infective endocarditis in childhood: 2015 update.Circulation. 2015; 132: 1487-1515Crossref PubMed Scopus (186) Google Scholar, Liu et al., 2011Liu 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.Clinical Infectious Diseases. 2011; 53: e18-e55Crossref Scopus (1896) Google Scholar). 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 et al., 2015Baltimore R.S. Gewitz M. Baddour L.M. Beerman L.B. Jackson M. Lockhart P.B. Willoughby Jr., R. Infective endocarditis in childhood: 2015 update.Circulation. 2015; 132: 1487-1515Crossref PubMed Scopus (186) Google Scholar, Hall Snyder et al., 2015Hall 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.Infectious Diseases and Therapy. 2015; 4: 51-65Crossref PubMed Scopus (32) Google Scholar). 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 et al., 2011Liu C. Bayer A. Cosgrove S.E.