Treatment of Methicillin-Resistant Staphylococcus aureus (MRSA) Infections in Children: a Reappraisal of Vancomycin

  • Roopali SharmaEmail author
  • Margaret R. Hammerschlag
Pediatric Infectious Diseases (I Brook, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Pediatric Infectious Diseases


Purpose of Review

In the last 50 years, vancomycin has been the agent of choice to treat infections due to methicillin-resistant Staphylococcus aureus (MRSA). However, vancomycin treatment failure is not uncommon, even when MRSA strains are fully susceptible to vancomycin. Treatment with vancomycin requires careful monitoring of drug levels as there is a potential for nephrotoxicity. Resistance to clindamycin is not infrequent, which also limits therapeutic options for treating infections due to MRSA in children. This paper reviews the current data on pharmacokinetics and pharmacodynamics and clinical efficacy of vancomycin in children.

Recent Findings

Resistance to vancomycin in MRSA (MIC >2 mg/L) is infrequent; there is increasing evidence in the literature that vancomycin maybe ineffective against increasing proportion of isolates with MICs between 1 and 2 mg/L. Recent studies and meta-analyses have demonstrated that strains with high vancomycin MICs are associated with poor outcomes especially in patients with bacteremia and deep tissue infections due to MRSA. This gradual increase in vancomycin MIC has been reported as MIC creep or vancomycin heteroresistance. Patients infected with MRSA isolates that exhibit MIC creep experience poorer clinical outcomes, including delayed treatment response, increased mortality, increase rate of relapse, and extended hospitalization. There are limited data to guide vancomycin dosing in children with MRSA. Although the vancomycin area under the curve AUC24/MIC ratio > 400 has been shown to predict clinical efficacy in adults, this relationship has not been documented very well for treatment outcomes in MRSA infections in children. Use of higher vancomycin dosages in attempts to achieve higher trough concentrations has been associated with increased nephrotoxicity.


New recently approved antibiotics including ceftaroline, dalbavancin, and tedizolid offer a number of advantages over vancomycin to treat staphylococcal infections: improved antimicrobial activity, superior pharmacokinetics, pharmacodynamics, tolerability, and dosing, including once-daily and weekly regimens, and less need for monitoring drug levels.


Vancomycin Staphylococcus aureus MRSA AUC24/MIC Heteroresistance Nephrotoxicity 


Compliance with Ethical Standards

Conflict of Interest

All authors declare no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Klein EY, Sun L, Smith DL, Laxminarayan R. The changing epidemiology of methicillin-resistant Staphylococcus aureus in the United States: a national observational study. Am J Epidemiol. 2013;177(7):666–74.CrossRefPubMedGoogle Scholar
  2. 2.
    David MZ, Daum RS. Community-associated methicillin-resistant Staphylococcus aureus: epidemiology and clinical consequences of an emerging epidemic. Clin Microbiol Rev. 2010;23(3):616–87.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Spagnolo AM, Panatto OD, Amicizia D. Staphylococcus aureus with reduced susceptibility to vancomycin in healthcare settings. J Prev Med Hyg. 2014;55:137–44.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Rybak MJ, LaPlante KL. Community-associated methicillin-resistant Staphylococcus aureus; a review. Pharmacotherapy. 2005;25:74–85.CrossRefPubMedGoogle Scholar
  5. 5.
    Patel M, Waites KB, Moser SA. Prevalence of inducible clindamycin resistance among community- and hospital-associated Staphylococcus aureus isolates. J Clin Microbiol. 2006;44(7):2481–4.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Chavez-Bueno S, Bozdogan B, Katz K. Inducible clindamycin resistance and molecular epidemiologic trends of pediatric community-acquired methicillin-resistant Staphylococcus aureus in Dallas, Texas. Antimicrob Agents Chemother. 2005;49(6):2283–8.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Howden BP, Davies JK, Johnson PD. Reduced vancomycin susceptibility in Staphylococcus aureus, including vancomycin-intermediate and heterogeneous vancomycin-intermediate strains: resistance mechanisms, laboratory detection, and clinical implications. Clin Microbiol Rev. 2010;23(1):99–139.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Cosgrove SE, Carroll KC, Perl TM. Staphylococcus aureus with reduced susceptibility to vancomycin. Clin Infect Dis. 2004;39(4):539–45.CrossRefPubMedGoogle Scholar
  9. 9.
    Kalil AC, Van Schooneveld TC, Fey PD, Rupp ME. Association between vancomycin minimum inhibitory concentration and mortality among patients with Staphylococcus aureus bloodstream infections: a systematic review and meta-analysis. JAMA. 2014;312:1552–64.CrossRefPubMedGoogle Scholar
  10. 10.
    Murray KP, Zhao JJ, Davis SL, Kullar R, Kaye KS, Lephart P, et al. Early use of daptomycin versus vancomycin for methicillin-resistant Staphylococcus aureus bacteremia with vancomycin minimum inhibitory concentration >1 mg/L: a matched cohort study. Clin Infect Dis. 2013;56:1562–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Wong-Beringer A, Joo J, Tse E, Beringer P. Vancomycin-associated nephrotoxicity: a critical appraisal of risk with high-dose therapy. Int J Antimicrob Agents. 2011;37:95–101.CrossRefPubMedGoogle Scholar
  12. 12.
    Van Hal SJ, Paterson DL, Lodise TP. Systematic review and meta-analysis of vancomycin-induced nephrotoxicity associated with dosing schedules that maintain troughs between 15 and 20 milligrams per liter. Antimicrob Agents Chemother. 2013;57:734–44.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Filippone EJ, Kraft WK, Farber JL. The nephrotoxicity of vancomycin. Clin Pharmacol Ther. 2017;102(3):459–69.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Gomes DM, Smotherman C, Birch A, Dpree L, Della Vecchia BJ, Kraemer DE, et al. Comparison of acute kidney injury during treatment with vancomycin in combination with piperacillin-tazobactam or cefepime. Pharmacotherapy. 2014;4:662–9.CrossRefGoogle Scholar
  15. 15.
    Moenster RP, Linneman TW, Finnegan PM, Hand S, Thomas Z, McDonald. Acute renal failure associated with vancomycin and β-lactams for the treatment of osteomyelitis in diabetics: piperacillin-tazobactam as compared with cefepime. Clin Microbiol Infect. 2014;20:O384–O38.CrossRefPubMedGoogle Scholar
  16. 16.
    Hammond DA, Smith MN, Painter JT, Meena NK. Comparative incidence of acute kidney injury in critically ill patients receiving vancomycin with concomitant piperacillin-tazobactam or cefepime: a retrospective cohort study. Pharmacotherapy. 2016;36:463–71.CrossRefPubMedGoogle Scholar
  17. 17.
    Giuliano C, Patel CR, Kale-Pradhan PB. Is the combination of piperacillin-tazobactam and vancomycin associated with development of acute kidney injury? A meta-analysis. Pharmacotherapy. 2017.
  18. 18.
    van Hal SJ, Lodise TP, Paterson DL. The clinical significance of vancomycin minimum inhibitory concentration in Staphylococcus aureus infections: a systematic review and meta-analysis. Clin Infect Dis. 2012;54:755–71.CrossRefPubMedGoogle Scholar
  19. 19.
    Song KH, Kim M, Kim JC. Impact of vancomycin MIC on treatment outcomes in invasive Staphylococcus aureus infections. Antimicrob Agents Chemother. 2017;61(3):e01845–16.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Soriano A, Marco F, Martinez JA, Pisos E, Almela M, Dimova VP, et al. Influence of vancomycin minimum inhibitory concentration on the treatment of methicillin-resistant Staphylococcus aureus bacteremia. Clin Infect Dis. 2008;46:193–200.CrossRefPubMedGoogle Scholar
  21. 21.
    Clinical and Laboratory Standards Institute (CLSI). Performance standards for antimicrobial susceptibility testing. 26th ed. CLSI supplement M100S. CLSI: Wayne, PA; 2016.Google Scholar
  22. 22.
    Kehrmann J, Kaase M, Szabados F, Gaterman SG, Buer J, Rath PM, et al. Vancomycin MIC creep in MRSA blood culture isolates from Germany: a regional problem? Eur J Clin Microbiol Infect Dis. 2011;30:677–83.CrossRefPubMedGoogle Scholar
  23. 23.
    Jones RN. Microbiological features of vancomycin in the 21st century: minimum inhibitory concentration creep, bactericidal/static activity, and applied breakpoints to predict clinical outcomes or detect resistant strains. Clin Infect Dis. 2006;42(Suppl 1):S13–24.CrossRefPubMedGoogle Scholar
  24. 24.
    Hawser SP, Bouchillon SK, Hoban DJ. Rising incidence of Staphylococcus aureus with reduced susceptibility to vancomycin and susceptibility to antibiotics: a global analysis 2004–2009. Int J Antimicrob Agents. 2011;37:219–24.CrossRefPubMedGoogle Scholar
  25. 25.
    Edwards B, Milne K, Lawes T. Is vancomycin MIC “creep” method dependent? Analysis of methicillin-resistant Staphylococcus aureus susceptibility trends in blood isolates from North East Scotland from 2006 to 2010. J Clin Microbiol. 2012;50(2):318–25.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Diaz R, Afreixo A, Ramalheira E. Evaluation of vancomycin MIC creep in methicillin-resistant Staphylococcus aureus infections-a systematic review and meta-analysis. Clin Microbiol Infect. 2018;24(2):97–104.CrossRefPubMedGoogle Scholar
  27. 27.
    Goldman JL, Harrison CJ, Al M. No evidence of vancomycin minimal inhibitory concentration creep or heteroresistance identified in pediatric Staphylococcus aureus blood isolates. Pediatr Infect Dis J. 2014;33(2):216–8.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, Gorwitz RJ, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:e18–55.CrossRefPubMedGoogle Scholar
  29. 29.
    Rybak M, Lomaestro B, Rotschafer JC, Moellering R Jr, Craig W, Billeter M, et al. 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. Am J Health Syst Pharm. 2009;66:82–98.CrossRefPubMedGoogle Scholar
  30. 30.
    Frymoyer A, Hersh AL, Benet LZ, Guglielmo BJ. Current recommended dosing of vancomycin for children with invasive methicillin-resistant Staphylococcus aureus infections is inadequate. Pediatr Infect Dis J. 2009;28(5):398–402.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Hsu AJ, Hamdy RF, Huang Y, Olson JA, Ghobrial S, Gerber JS, et al. Vancomycin trough concentrations and duration of methicillin- resistant Staphylococcus aureus bacteremia in children. J Pediatric Infect Dis Soc. 2018 Dec 3;7(4):338–41. Scholar
  32. 32.
    Le J, Bradley JS, Murray W. Improved vancomycin dosing in children using area-cnder-the-curve exposure. Pediatr Infect Dis J. 2013;32(4):e155–63.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Hoang J, Dersch-Mills D, Bresee L. Achieving therapeutic vancomycin levels in pediatric patients. Can J Hosp Pharm. 2014;67(6):416–22.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Benner KW, Worthington MA, Kimberlin DW, Hill K, Buckley K, Tofil NM. Correlation of vancomycin dosing to serum concentrations in pediatric patients: a retrospective database review. J Pediatr Pharmacol Ther. 2009;14(2):86–93.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Glover ML, Cole E, Wolfsdorf J. Vancomycin dosage requirements among pediatric intensive care unit patients with normal renal function. J Crit Care. 2000;15(1):1–4.CrossRefPubMedGoogle Scholar
  36. 36.
    Frymoyer A, Hersh AL, Coralic Z, Benet LZ, Guglielmo BJ. Prediction of vancomycin pharmacodynamics in children with invasive methicillin- resistant Staphylococcus aureus infections: a Monte Carlo simulation. Clin Ther. 2010;32(3):534–42.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Geerlof LM, Boucher J. Evaluation of vancomycin dosing and corresponding drug concentrations in pediatric patients. Hospital Pediatrics. 2014;4:342–7. Scholar
  38. 38.
    Durham SH, Simmons ML, Mulherin DW, Foland JA. An evaluation of vancomycin dosing for complicated infections in pediatric patients. Hospital Pediatrics. 2015;5:276–81. Scholar
  39. 39.
    Frymoyer A, Guglielmo BJ, Hersh AL. Desired vancomycin trough serum concentration for treating invasive methicillin-resistant staphylococcal infections. Pediatr Infect Dis J. 2013;32(10):1077–9.CrossRefPubMedGoogle Scholar
  40. 40.
    Hwang D, Chang-Nan C, Chang L, Peng CC. Vancomycin dosing and target attainment in children. J Microbiol Immunol Infect. 2017;50(4):494–9.CrossRefPubMedGoogle Scholar
  41. 41.
    Chhim RF, Arnold SR, Lee KR. Vancomycin dosing practices, trough concentrations, and predicted area under the curve in children with suspected invasive staphylococcal nfections. J Pediatr Infect Dis Soc. 2013;2(3):259–62.CrossRefGoogle Scholar
  42. 42.
    •• Silva Alves GC, Dutra da Silva S, Ftade VP, Rorigues D, Baldoni AO, de Castro WV, et al. Determining the optimal vancomycin daily dose for pediatrics: a meta-analysis. Eur J Clin Pharmacol. 2017;73(11):1341–53. Important meta-analysis summarizing vancomycin daily dose in pediatric patients. CrossRefPubMedGoogle Scholar
  43. 43.
    Hale CM, Seabury RW, Steele JM, Darko W, Miller CD. Are vancomycin trough concentrations of 15 to 20 mg/L associated with increased attainment of an AUC/MIC ≥ 400 in patients with presumed MRSA infection? J Pharm Pract. 2017;30(3):329–35. Scholar
  44. 44.
    Kishk OA, Lardieri AB, Heil EL, Morgan JA. Vancomycin AUC/MIC and corresponding troughs in a pediatric population. J Pediatr Pharmacol Ther. 2017;22(1):41–7.PubMedPubMedCentralGoogle Scholar
  45. 45.
    •• Fiorito TM, Luther MK, Dennehy PH, LaPlante KL, Matson KL. Nephrotoxicity with vancomycin in the pediatric population: a systematic review and meta-analysis. Pediatr Infect Dis J. 2018;37(7):654–61. Important meta-analysis summarizing nephrotoxicity in pediatric patients. CrossRefPubMedGoogle Scholar
  46. 46.
    Turner RB, Kojiro K, Shephard EA, Won R, Chang E, Chan D, et al. Review and validation of Bayesian dose-optimizing software and equations for calculation of vancomycin area under the curve in critically ill patients. Pharmacotherapy. 2018;38(12):1174–83.CrossRefPubMedGoogle Scholar
  47. 47.
    Neely MN, Kato L, Youn G, Kraler L, Bayard D, van Guilder M, et al. Prospective trial on the use of trough concentration versus area under the curve to determine therapeutic vancomycin dosing. Antimicrob Agents Chemother. 2018;62(2):e02042–17. Scholar
  48. 48.
    •• Randolph AG, Xu R, Novak T, Newhams MM, Wardenburg JB, Weiss SL, et al. Vancomycin monotherapy may be insufficient to treat methicillin-resistant Staphylococcus aureus coinfection in children with influenza-related illness. Clin Infect Dis. 2019;68(3):365–72. Important clinical study demonstrating poor outcome in children who were treated with vancomycin alone.CrossRefPubMedGoogle Scholar
  49. 49.
    Stein GE, Wells EM. The importance of tissue penetration in achieving successful antimicrobial treatment of nosocomial pneumoniae and complicated skin and soft-tissue infections caused by methicillin-resistant Staphylococcus aureus: vancomycin and linezolid. Curr Med Res Opin. 2010;25:571–88.CrossRefGoogle Scholar
  50. 50.
    Geriak M, Haddad F, Rizvi K, Rose W, Kullar R, LaPlante K, et al. Clinical data on daptomycin plus ceftaroline versus standard of care monotherapy in the treatment of methicillin-resistant Staphylococcus aureus bacteremia. Antimicrob Agents Chemother. 2019;63:e02483–18.CrossRefPubMedGoogle Scholar
  51. 51.
    • Sutter DE, Milburn F, Chukwuma U, Dzialowy N, Maranich AM, Hospenthal DR. Changing susceptibility of Staphylococcus aureus in a US pediatric population. Pediatrics. 2016;137:e20153099. Survey demonstrating increasing significant levels of clindamycin resistance among S. aureus isolates from children in the USA.CrossRefPubMedGoogle Scholar
  52. 52.
    Cies JJ, Moore WS 2nd, Enache A, Chopra A. Ceftaroline for suspected confirmed invasive methicillin-resistant Staphylococcus aureus: a pharmacokinetic case series. Pediatr Crit Care Med. 2018;19:e292–9.CrossRefPubMedGoogle Scholar
  53. 53.
    Sharma R, Francois D, Hammerschlag MR. New antimicrobial agents for the treatment of staphylococcal infections in children. Pediatr Clin N Am. 2017;64:1369–87.CrossRefGoogle Scholar
  54. 54.
    McNeil JC, Kaplan SL, Vallejo JG. The influence of the route of antibiotic administration, methicillin susceptibility, vancomycin duration and serum trough concentration on outcomes of pediatric Staphylococcus aureus bacteremic osteoarticular infection. Pediatr Infect Dis. 2017;36:572–7.CrossRefGoogle Scholar
  55. 55.
    Krok EY, Vallejo J, Sommer LM, Rosas L, Kaplan SL, Hulten KG, et al. Association of vancomycin MIC and molecular characteristics with clinical outcomes in methicillin-susceptible Staphylococcus aureus acute hematogenous osteoarticular infections in children. Antimicrob Agents Chemother. 2018;62:1–10.Google Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmacy PracticeTouro College of PharmacyNew YorkUSA
  2. 2.Department of PharmacyDownstate Medical CenterBrooklynUSA
  3. 3.Department of Pediatrics, Division of Infectious DiseasesState University of New York Downstate Medical CenterBrooklynUSA

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