Manipulating the microbiome: evolution of a strategy to prevent S. aureus disease in children


Hospitalized infants have the highest rates of invasive Staphylococcus aureus disease of any population and infection control strategies such as decolonization have been insufficient. For decades, researchers began studying the microbiome in search of new prevention strategies. The resident microbiota was found to be closely associated with susceptibility and at times, resistance to S. aureus colonization. The evolution of nucleic acid based techniques has enhanced our understanding of the complex relationship between the nasal microbiota and S. aureus colonization. We review what is known about bacterial communities in the nasal cavity of infants and discuss how future microbiome studies may help identify novel interventions to protect high-risk infants from S. aureus disease.

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Figure 1


  1. 1

    Laupland KB, Lyytikainen O, Sogaard M, Kennedy KJ, Knudsen JD, Ostergaard C et al. The changing epidemiology of Staphylococcus aureus bloodstream infection: a multinational population-based surveillance study. Clin Microbiol Infect 2013; 19 (5): 465–471.

    CAS  Article  Google Scholar 

  2. 2

    Hocevar SN, Edwards JR, Horan TC, Morrell GC, Iwamoto M, Lessa FC . Device-associated infections among neonatal intensive care unit patients: incidence and associated pathogens reported to the National Healthcare Safety Network, 2006-2008. Infect Control Hosp Epidemiol 2012; 33 (12): 1200–1206.

    Article  Google Scholar 

  3. 3

    Humphreys H, Becker K, Dohmen PM, Petrosillo N, Spencer M, van Rijen M et al. Staphylococcus aureus and surgical site infections: benefits of screening and decolonization before surgery. J Hosp Infect 2016; 94 (3): 295–304.

    CAS  Article  Google Scholar 

  4. 4

    Larru B, Gong W, Vendetti N, Sullivan KV, Localio R, Zaoutis TE et al. Bloodstream infections in hospitalized children: epidemiology and antimicrobial susceptibilities. Pediatr Infect Dis J 2016; 35 (5): 507–510.

    Article  Google Scholar 

  5. 5

    Weidenmaier C, Goerke C, Wolz C . Staphylococcus aureus determinants for nasal colonization. Trends Microbiol 2012; 20 (5): 243–250.

    CAS  Article  Google Scholar 

  6. 6

    von Eiff C, Becker K, Machka K, Stammer H, Peters G . Nasal carriage as a source of Staphylococcus aureus bacteremia. Study Group. N Engl J Med 2001; 344 (1): 11–16.

    CAS  Article  Google Scholar 

  7. 7

    Kluytmans JA, Wertheim HF . Nasal carriage of Staphylococcus aureus and prevention of nosocomial infections. Infection 2005; 33 (1): 3–8.

    CAS  Article  Google Scholar 

  8. 8

    Popoola VO, Colantuoni E, Suwantarat N, Pierce R, Carroll KC, Aucott SW et al. Active surveillance cultures and decolonization to reduce Staphylococcus aureus infections in the neonatal intensive care unit. Infect Control Hosp Epidemiol 2016; 37 (4): 381–387.

    Article  Google Scholar 

  9. 9

    Light IJ, Walton R, Sutherland JM, Shinefield HR, Brackvogel V . Use of bacterial interference to control a staphylococcal nursery outbreak: deliberate colonization of all infants with the 502a strain of Staphylococcus aureus. Am J Dis Child 1967 113 (3): 291–300.

  10. 10

    Popoola VO, Milstone AM . Decolonization to prevent Staphylococcus aureus transmission and infections in the neonatal intensive care unit. J Perinatol 2014; 34 (11): 805–810.

    CAS  Article  Google Scholar 

  11. 11

    Zingg W, Hopkins S, Gayet-Ageron A, Holmes A, Sharland M, Suetens C . Health-care-associated infections in neonates, children, and adolescents: an analysis of paediatric data from the European Centre for Disease Prevention and Control point-prevalence survey. Lancet Infect Dis 2017; 17 (4): 381–389.

    Article  Google Scholar 

  12. 12

    Dantes R, Mu Y, Belflower R, Aragon D, Dumyati G, Harrison LH et al. National burden of invasive methicillin-resistant Staphylococcus aureus infections, United States, 2011. JAMA Int Med 2013; 173 (21): 1970–1978.

    Google Scholar 

  13. 13

    Ericson JE, Popoola VO, Smith PB, Benjamin DK, Fowler VG, Benjamin DK Jr. et al. Burden of Invasive Staphylococcus aureus Infections in hospitalized infants. JAMA Pediatr 2015; 169 (12): 1105–1111.

    Article  Google Scholar 

  14. 14

    Iwamoto M, Mu Y, Lynfield R, Bulens SN, Nadle J, Aragon D et al. Trends in invasive methicillin-resistant Staphylococcus aureus infections. Pediatrics 2013; 132 (4): e817–e824.

    Article  Google Scholar 

  15. 15

    Reich PJ, Boyle MG, Hogan PG, Johnson AJ, Wallace MA, Elward AM et al. Emergence of community-associated methicillin-resistant Staphylococcus aureus strains in the neonatal intensive care unit: an infection prevention and patient safety challenge. Clin Microbiol Infect 2016; 22 (7): 645 e641–645 e648.

    Article  Google Scholar 

  16. 16

    Chen HW, Liu PF, Liu YT, Kuo S, Zhang XQ, Schooley RT et al. Nasal commensal Staphylococcus epidermidis counteracts influenza virus. Sci Rep 2016; 6: 27870.

    CAS  Article  Google Scholar 

  17. 17

    Shinefield HR, Sutherland JM, Ribble JC, Eichenwald HF . Bacterial interference: its effect on nursery-acquired infection with Staphylococcus aureus. II. The Ohio epidemic. Am J Dis Child 1963; 105: 655–662.

    CAS  PubMed  Google Scholar 

  18. 18

    Shinefield HR, Ribble JC, Boris M, Eichenwald HF . Bacterial interference: its effect on nursery-acquired infection with Staphylococcus aureus. I. Preliminary observations on artificial colonzation of newborns. Am J Dis Child 1963; 105: 646–654.

    CAS  PubMed  Google Scholar 

  19. 19

    Houck PW, Nelson JD, Kay JL . Fatal septicemia due to Staphylococcus aureus 502a: Report of a case and review of the infectious complications of bacterial interference programs. Am J Dis Child 1972; 123 (1): 45–48.

    CAS  Article  Google Scholar 

  20. 20

    Light IJ, Sutherland JM, Schott JE . Control of a staphylococcal outbreak in a nursery: use of bacterial interference. JAMA 1965; 193 (9): 699–704.

    CAS  Article  Google Scholar 

  21. 21

    Shinefield HR, Ribble JC, Boris M . Bacterial interference between strains of Staphylococcus aureus, 1960 to 1970. Am J Dis Child 1971; 121 (2): 148–152.

    CAS  PubMed  Google Scholar 

  22. 22

    Barbagelata MS, Alvarez L, Gordiola M, Tuchscherr L, von Eiff C, Becker K et al. Auxotrophic mutant of Staphylococcus aureus interferes with nasal colonization by the wild type. Microbes Infect 2011; 13 (12-13): 1081–1090.

    CAS  Article  Google Scholar 

  23. 23

    Iwase T, Uehara Y, Shinji H, Tajima A, Seo H, Takada K et al. Staphylococcus epidermidis Esp inhibits Staphylococcus aureus biofilm formation and nasal colonization. Nature 2010; 465 (7296): 346–349.

    CAS  Article  Google Scholar 

  24. 24

    Zipperer A, Konnerth MC, Laux C, Berscheid A, Janek D, Weidenmaier C et al. Human commensals producing a novel antibiotic impair pathogen colonization. Nature 2016; 535 (7613): 511–516.

    CAS  Article  Google Scholar 

  25. 25

    Uehara Y, Nakama H, Agematsu K, Uchida M, Kawakami Y, Abdul Fattah AS et al. Bacterial interference among nasal inhabitants: eradication of Staphylococcus aureus from nasal cavities by artificial implantation of Corynebacterium sp. J Hosp Infect 2000; 44 (2): 127–133.

    CAS  Article  Google Scholar 

  26. 26

    Ramsey MM, Freire MO, Gabrilska RA, Rumbaugh KP, Lemon KP . Staphylococcus aureus shifts toward commensalism in response to Corynebacterium species. Front Microbiol 2016; 7: 1230.

    Article  Google Scholar 

  27. 27

    Kiryukhina NV, Melnikov VG, Suvorov AV, Morozova YA, Ilyin VK . Use of Corynebacterium pseudodiphtheriticum for elimination of Staphylococcus aureus from the nasal cavity in volunteers exposed to abnormal microclimate and altered gaseous environment. Probiotics Antimicrob Proteins 2013; 5 (4): 233–238.

    CAS  Article  Google Scholar 

  28. 28

    Sullivan SB, Kamath S, McConville TH, Gray BT, Lowy FD, Gordon PG et al. Staphylococcus epidermidis protection against Staphylococcus aureus colonization in people living with human immunodeficiency virus in an inner-city outpatient population: a cross-sectional study. Open Forum Infect Dis 2016; 3 (4): ofw234.

    Article  Google Scholar 

  29. 29

    Park B, Iwase T, Liu GY . Intranasal application of S. epidermidis prevents colonization by methicillin-resistant Staphylococcus aureus in mice. PLoS ONE 2011; 6 (10): e25880.

    CAS  Article  Google Scholar 

  30. 30

    Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M et al. Diversity of the human intestinal microbial flora. Science 2005; 308 (5728): 1635–1638.

    Article  Google Scholar 

  31. 31

    Liu CM, Price LB, Hungate BA, Abraham AG, Larsen LA, Christensen K et al. Staphylococcus aureus and the ecology of the nasal microbiome. Sci Adv 2015; 1 (5): e1400216.

    Article  Google Scholar 

  32. 32

    Alvarez AS, Remy L, Allix-Beguec C, Ligier C, Dupont C, Leminor O et al. Patient nostril microbial flora: individual-dependency and diversity precluding prediction of Staphylococcus aureus acquisition. Clin Microbiol Infect 2014; 20 (1): 70–78.

    CAS  Article  Google Scholar 

  33. 33

    Frank DN, Feazel LM, Bessesen MT, Price CS, Janoff EN, Pace NR . The human nasal microbiota and Staphylococcus aureus carriage. PLoS ONE 2010; 5 (5): e10598.

    Article  Google Scholar 

  34. 34

    Johnson RC, Ellis MW, Lanier JB, Schlett CD, Cui T, Merrell DS . Correlation between nasal microbiome composition and remote purulent skin and soft tissue infections. Infect Immun 2015; 83 (2): 802–811.

    Article  Google Scholar 

  35. 35

    Yan M, Pamp SJ, Fukuyama J, Hwang PH, Cho DY, Holmes S et al. Nasal microenvironments and interspecific interactions influence nasal microbiota complexity and S. aureus carriage. Cell Host Microbe 2013; 14 (6): 631–640.

    CAS  Article  Google Scholar 

  36. 36

    Bessesen MT, Kotter CV, Wagner BD, Adams JC, Kingery S, Benoit JB et al. MRSA colonization and the nasal microbiome in adults at high risk of colonization and infection. J Infect 2015; 71 (6): 649–657.

    Article  Google Scholar 

  37. 37

    Petchey OL, Eklof A, Borrvall C, Ebenman B . Trophically unique species are vulnerable to cascading extinction. Am Nat 2008; 171 (5): 568–579.

    Article  Google Scholar 

  38. 38

    Arrieta M-C, Stiemsma LT, Amenyogbe N, Brown EM, Finlay B . The intestinal microbiome in early life: health and disease. Front Immunol 2014; 5: 427.

    Article  Google Scholar 

  39. 39

    Oh J, Conlan S, Polley EC, Segre JA, Kong HH . Shifts in human skin and nares microbiota of healthy children and adults. Genome Med 2012; 4 (10): 77–77.

    Article  Google Scholar 

  40. 40

    Wos-Oxley ML, Plumeier I, von Eiff C, Taudien S, Platzer M, Vilchez-Vargas R et al. A poke into the diversity and associations within human anterior nare microbial communities. ISME J 2010; 4 (7): 839–851.

    Article  Google Scholar 

  41. 41

    Cremers AJH, Zomer AL, Gritzfeld JF, Ferwerda G, van Hijum SAFT, Ferreira DM et al. The adult nasopharyngeal microbiome as a determinant of pneumococcal acquisition. Microbiome 2014; 2: 44.

    Article  Google Scholar 

  42. 42

    Peterson SW, Knox NC, Golding GR, Tyler SD, Tyler AD, Mabon P et al. A study of the infant nasal microbiome development over the first year of life and in relation to their primary adult caregivers using cpn60 universal target (UT) as a phylogenetic marker. PLoS ONE 2016; 11 (3): e0152493.

    Article  Google Scholar 

  43. 43

    Mueller NT, Bakacs E, Combellick J, Grigoryan Z, Dominguez-Bello MG . The infant microbiome development: mom matters. Trends Mol Med 2015; 21 (2): 109–117.

    Article  Google Scholar 

  44. 44

    Biesbroek G, Tsivtsivadze E, Sanders EA, Montijn R, Veenhoven RH, Keijser BJ et al. Early respiratory microbiota composition determines bacterial succession patterns and respiratory health in children. Am J Respir Crit Care Med 2014; 190 (11): 1283–1292.

    Article  Google Scholar 

  45. 45

    Dominguez-Bello MG, Costello EK, Contreras M, Magris M, Hidalgo G, Fierer N et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci USA 2010; 107 (26): 11971–11975.

    Article  Google Scholar 

  46. 46

    Belkaid Y, Hand T . Role of the microbiota in Immunity and inflammation. Cell 2014; 157 (1): 121–141.

    CAS  Article  Google Scholar 

  47. 47

    Hilty M, Qi W, Brugger SD, Frei L, Agyeman P, Frey PM et al. Nasopharyngeal microbiota in infants with acute otitis media. J Infect Dis 2012; 205 (7): 1048–1055.

    CAS  Article  Google Scholar 

  48. 48

    Biesbroek G, Bosch AA, Wang X, Keijser BJ, Veenhoven RH, Sanders EA et al. The impact of breastfeeding on nasopharyngeal microbial communities in infants. Am J Respir Crit Care Med 2014; 190 (3): 298–308.

    PubMed  Google Scholar 

  49. 49

    Biesbroek G, Wang X, Keijser BJF, Eijkemans RMJ, Trzciński K, Rots NY et al. Seven-valent pneumococcal conjugate vaccine and nasopharyngeal microbiota in healthy children. Emerg Infect Dis 2014; 20 (2): 201–210.

    Article  Google Scholar 

  50. 50

    Bogaert D, Keijser B, Huse S, Rossen J, Veenhoven R, van Gils E et al. Variability and diversity of nasopharyngeal microbiota in children: a metagenomic analysis. PLoS ONE 2011; 6 (2): e17035.

    CAS  Article  Google Scholar 

  51. 51

    Sassone-Corsi M, Raffatellu M . No Vacancy: how beneficial microbes cooperate with immunity to provide colonization resistance to pathogens. J Immunol 2015; 194 (9): 4081–4087.

    CAS  Article  Google Scholar 

  52. 52

    Stearns JC, Davidson CJ, McKeon S, Whelan FJ, Fontes ME, Schryvers AB et al. Culture and molecular-based profiles show shifts in bacterial communities of the upper respiratory tract that occur with age. ISME J 2015; 9 (5): 1246–1259.

    Article  Google Scholar 

  53. 53

    Yu LC-H Shih Y-A, Wu L-L, Lin Y-D, Kuo W-T, Peng W-H et al. Enteric dysbiosis promotes antibiotic-resistant bacterial infection: systemic dissemination of resistant and commensal bacteria through epithelial transcytosis. Am J Physiol Gastrointest Liver Physiol 2014; 307 (8): G824–G835.

    Article  Google Scholar 

  54. 54

    Laufer AS, Metlay JP, Gent JF, Fennie KP, Kong Y, Pettigrew MM . Microbial communities of the upper respiratory tract and otitis media in children. mBio 2011; 2 (1): e00245–00310.

    Article  Google Scholar 

  55. 55

    Bogaert D, De Groot R, Hermans PW . Streptococcus pneumoniae colonisation: the key to pneumococcal disease. Lancet Infect Dis 2004; 4 (3): 144–154.

    CAS  Article  Google Scholar 

  56. 56

    Kim Y, Koh I, Rho M . Deciphering the human microbiome using next-generation sequencing data and bioinformatics approaches. Methods (San Diego, Calif) 2015; 79-80: 52–59.

    CAS  Article  Google Scholar 

  57. 57

    Burnham CA, Hogan PG, Wallace MA, Deych E, Shannon W, Warren DK et al. Topical decolonization does not eradicate the skin microbiota of community-dwelling or hospitalized adults. Antimicrob Agents Chemother 2016; 60 (12): 7303–7312.

    CAS  PubMed  PubMed Central  Google Scholar 

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This work was supported in part by the Agency for Healthcare Research and Quality R01HS022872.

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Correspondence to A M Milstone.

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Khamash, D., Voskertchian, A. & Milstone, A. Manipulating the microbiome: evolution of a strategy to prevent S. aureus disease in children. J Perinatol 38, 105–109 (2018).

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