Antibiotic Resistances of Clostridium difficile

  • Patrizia SpigagliaEmail author
  • Paola Mastrantonio
  • Fabrizio Barbanti
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1050)


The rapid evolution of antibiotic resistance in Clostridium difficile and the consequent effects on prevention and treatment of C. difficile infections (CDIs) are matter of concern for public health. Antibiotic resistance plays an important role in driving C. difficile epidemiology. Emergence of new types is often associated with the emergence of new resistances and most of epidemic C. difficile clinical isolates is currently resistant to multiple antibiotics. In particular, it is to worth to note the recent identification of strains with reduced susceptibility to the first-line antibiotics for CDI treatment and/or for relapsing infections. Antibiotic resistance in C. difficile has a multifactorial nature. Acquisition of genetic elements and alterations of the antibiotic target sites, as well as other factors, such as variations in the metabolic pathways and biofilm production, contribute to the survival of this pathogen in the presence of antibiotics. Different transfer mechanisms facilitate the spread of mobile elements among C. difficile strains and between C. difficile and other species. Furthermore, recent data indicate that both genetic elements and alterations in the antibiotic targets can be maintained in C. difficile regardless of the burden imposed on fitness, and therefore resistances may persist in C. difficile population in absence of antibiotic selective pressure.


C. difficile Antibiotic susceptibility methods Mechanisms of resistance Multi-drug resistance (MDR) 


  1. Ackermann G, Tang YJ, Kueper R et al (2001) Resistance to moxifloxacin in toxigenic Clostridium difficile isolates is associated with mutations in gyr A. Antimicrob Agents Chemother 45:2348–2353PubMedPubMedCentralCrossRefGoogle Scholar
  2. Ackermann G, Tang-Feldman YJ, Schaumann R et al (2003) Antecedent use of fluoroquinolones is associated with resistance to moxifloxacin in Clostridium difficile. Clin Microbiol Infect 9:526–530PubMedCrossRefGoogle Scholar
  3. Adler A, Miller-Roll T, Bradenstein R, Block C et al (2015) A national survey of the molecular epidemiology of Clostridium difficile in Israel: the dissemination of the ribotype 027 strain with reduced susceptibility to vancomycin and metronidazole. Diagn Microbiol Infect Dis 83:21–24PubMedCrossRefGoogle Scholar
  4. Álvarez-Pérez S, Blanco JL, Harmanus C et al (2017) Subtyping and antimicrobial susceptibility of Clostridium difficile PCR ribotype 078/126 isolates of human and animal origin. Vet Microbiol 199:15–22CrossRefPubMedGoogle Scholar
  5. Ambrose NS, Johnson M, Burdon D et al (1985) The influence of single dose intravenous antibiotics on faecal flora and emergence of Clostridium difficile. J Antimicrob Chemother 15:319–326PubMedCrossRefGoogle Scholar
  6. Ammam F, Marvaud JC, Lambert T (2012) Distribution of the vanG-like gene cluster in Clostridium difficile clinical isolates. Can J Microbiol 58:547–551PubMedCrossRefGoogle Scholar
  7. Ammam F, Meziane-Cherif D, Mengin-Lecreulx D et al (2013) The functional vanGCd cluster of Clostridium difficile does not confer vancomycin resistance. Mol Microbiol 89:612–625PubMedCrossRefGoogle Scholar
  8. Baines SD, O’Connor R, Freeman J et al (2008) Emergence of reduced susceptibility to metronidazole in Clostridium difficile. J Antimicrob Chemother 62:1046–1052CrossRefPubMedGoogle Scholar
  9. Baldan R, Trovato A, Bianchini V et al (2015) A successful epidemic genotype: Clostridium difficile PCR ribotype 018. J Clin Microbiol 53:2575–2580PubMedPubMedCentralCrossRefGoogle Scholar
  10. Bartlett JG, Onderdonk AB, Cisneros RL et al (1977) Clindamycin-associated colitis due to a toxin-producing species of Clostridium in hamsters. J Infect Dis 136:701–705PubMedCrossRefGoogle Scholar
  11. Bauer MP, Notermans DW, van Benthem BHB et al (2011) Clostridium difficile infection in Europe: a hospital-based survey. Lancet 377:63–73PubMedPubMedCentralCrossRefGoogle Scholar
  12. Bignardi GE (1998) Risk factors for Clostridium difficile infection. J Hosp Infect 40:1–15PubMedCrossRefGoogle Scholar
  13. Bolton RP, Culshaw MA (1986) Faecal metronidazole concentrations during oral and intravenous therapy for antibiotic associated colitis due to Clostridium difficile. Gut 27:1169–1172PubMedPubMedCentralCrossRefGoogle Scholar
  14. Brazier JS, Fawley W, Freeman J et al (2001) Reduced susceptibility of Clostridium difficile to metronidazole. J Antimicrob Chemother 48:741–742PubMedCrossRefGoogle Scholar
  15. Brouwer MSM, Warburton PJ, Roberts AP et al (2011) Genetic organisation, mobility and predicted functions of genes on integrated, mobile genetic elements in sequenced strains of Clostridium difficile. PLoS One 6:e23014PubMedPubMedCentralCrossRefGoogle Scholar
  16. Brouwer MSM, Roberts AP, Mullany P et al (2012) In silico analysis of sequenced strains of Clostridium difficile reveals a related set of conjugative transposons carrying a variety of accessory genes. Mob Genet Elem 2:8–12CrossRefGoogle Scholar
  17. Büchler AC, Rampini SK, Stelling S et al (2014) Antibiotic susceptibility of Clostridium difficile is similar worldwide over two decades despite widespread use of broad-spectrum antibiotics: an analysis done at the University Hospital of Zurich. BMC Infect Dis 14:607PubMedPubMedCentralCrossRefGoogle Scholar
  18. Burckhardt F, Friedrich A, Beier D et al (2008) Clostridium difficile surveillance trends, Saxony, Germany. Emerg Infect Dis 4:691–692CrossRefGoogle Scholar
  19. Cairns MD, Preston MD, Hall CL et al (2017) Comparative genome analysis and global phylogeny of the toxin variant Clostridium difficile PCR ribotype 017 reveals the evolution of two independent sublineages. J Clin Microbiol 55:865–876PubMedPubMedCentralCrossRefGoogle Scholar
  20. Candela T, Marvaud J-C, Nguyen TK et al (2017) A cfr-like Gene cfr(C) conferring linezolid resistance is common in Clostridium difficile. Int J Antimicrob Agents.
  21. Carman RJ, Genheimer CW, Rafii F et al (2009) Diversity of moxifloxacin resistance during a nosocomial outbreak of a predominantly ribotype ARU 027 Clostridium difficile diarrhea. Anaerobe 15:244–248PubMedCrossRefGoogle Scholar
  22. Carman RJ, Boone JH, Grover H et al (2012) In vivo selection of rifamycin-resistant Clostridium difficile during rifaximin therapy. Antimicrob Agents Chemother 56:6019–6020PubMedPubMedCentralCrossRefGoogle Scholar
  23. Chaparro-Rojas F, Mullane KM (2013) Emerging therapies for Clostridium difficile infection – focus on fidaxomicin. Infect Drug Resist 6:41–53PubMedPubMedCentralGoogle Scholar
  24. Chia JH, Lai HC, Su LH et al (2013) Molecular epidemiology of Clostridium difficile at a medical center in Taiwan: persistence of genetically clustering of A−B+ isolates and increase of A+B+ isolates. PLoS One 8:e75471PubMedPubMedCentralCrossRefGoogle Scholar
  25. Chong PM, Lynch T, McCorrister S et al (2014) Proteomic analysis of a NAP1 Clostridium difficile clinical isolate resistant to metronidazole. PLoS One 9:e82622PubMedPubMedCentralCrossRefGoogle Scholar
  26. Clements AC, Magalhães RJ, Tatem AJ et al (2010) Clostridium difficile PCR ribotype 027: assessing the risks of further worldwide spread. Lancet Infect Dis 10:395–404PubMedCrossRefGoogle Scholar
  27. Clinical and Laboratory Standards Institute (CLSI) (2012) Methods for antimicrobial susceptibility testing of anaerobic bacteria. Approved standard-eighth edn. CLSI document M11-A8. ISBN 1-56238-789-8 (Print); ISBN 1-56238-790-1 (Electronic)Google Scholar
  28. Clinical and Laboratory Standards Institute (CLSI) (2015) Performance standards for antimicrobial susceptibility testing. Twenty-fifth informational supplement. CLSI document M100-S25. ISBN 1-56238-989-0 (Print); ISBN 1-56238-990-4 (Electronic)Google Scholar
  29. Corver J, Bakker D, Brouwer MSM et al (2012) Analysis of a Clostridium difficile PCR ribotype 078 100 kilobase island reveals the presence of a novel transposon, Tn6164. BMC Microbiol 12:130PubMedPubMedCentralCrossRefGoogle Scholar
  30. Curry SR, Marsh JW, Shutt KA et al (2009) High frequency of rifampin resistance identified in an epidemic Clostridium difficile clone from a large teaching hospital. Clin Infect Dis 48:425–429PubMedPubMedCentralCrossRefGoogle Scholar
  31. Dapa T, Leuzzi R, Ng YK et al (2013) Multiple factors modulate biofilm formation by the anaerobic pathogen Clostridium difficile. J Bacteriol 195:545–555PubMedCrossRefGoogle Scholar
  32. Davies KA, Longshaw CM, Davis GL et al (2014) Underdiagnosis of Clostridium difficile across Europe: the European, multicentre, prospective, biannual, point-prevalence study of Clostridium difficile infection in hospitalised patients with diarrhoea (EUCLID). Lancet Infect Dis 14:1208–1219PubMedPubMedCentralCrossRefGoogle Scholar
  33. de Lalla F, Privitera G, Ortisi G et al (1989) Third generation cephalosporins as a risk factor for Clostridium difficile-associated disease: a four-year survey in a general hospital. J Antimicrob Chemother 23:623–631PubMedCrossRefGoogle Scholar
  34. Debast SB, Bauer MP, Kuijper EJ (2014) European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection. Clin Microbiol Infect 20:1–26PubMedPubMedCentralCrossRefGoogle Scholar
  35. Dingle KE, Elliott B, Robinson E et al (2014) Evolutionary history of the Clostridium difficile pathogenicity locus. Genome Biol Evol 6:36–52PubMedPubMedCentralCrossRefGoogle Scholar
  36. Dong D, Zhang L, Chen X et al (2013) Antimicrobial susceptibility and resistance mechanisms of clinical Clostridium difficile from a Chinese tertiary hospital. Int J Antimicrob Agents 41:80–84PubMedCrossRefGoogle Scholar
  37. Dong D, Chen X, Jiang C et al (2014) Genetic analysis of Tn916-like elements conferring tetracycline resistance in clinical isolates of Clostridium difficile. Int J of Antimicrob Agents 43:73–77CrossRefGoogle Scholar
  38. Dridi L, Tankovic J, Burghoffer B et al (2002) Gyr A and gyrB mutations are implicated in cross-resistance to ciprofloxacin and moxifloxacin in Clostridium difficile. Antimicrob Agents Chemother 46:3418–3421PubMedPubMedCentralCrossRefGoogle Scholar
  39. Drudy D, Quinn T, O’Mahony R et al (2006) High-level resistance to moxifloxacin and gatifloxacin associated with a novel mutation in gyrB in toxin-A-negative, toxin-B-positive Clostridium difficile. J Antimicrob Chemother 58:1264–1267PubMedCrossRefGoogle Scholar
  40. Drudy D, Kyne L, O’Mahony R et al (2007) gyrA mutations in fluoroquinolone-resistant Clostridium difficile PCR-027. Emerg Infect Dis 13:504–505PubMedPubMedCentralCrossRefGoogle Scholar
  41. Dubberke ER, Olsen MA (2012) Burden of Clostridium difficile on the healthcare system. Clin Infect Dis 55(suppl 2):S88–S92PubMedPubMedCentralCrossRefGoogle Scholar
  42. Eckert C, Coignard B, Hebert M et al (2013) Clinical and microbiological features of Clostridium difficile infections in France: the ICD-RAISIN 2009 national survey. Méd Mal Infect 43:67–74PubMedCrossRefGoogle Scholar
  43. Eitel Z, Terhes G, Sóki J et al (2015) Investigation of the MICs of fidaxomicin and other antibiotics against Hungarian Clostridium difficile isolates. Anaerobe 31:47–49PubMedCrossRefGoogle Scholar
  44. Erikstrup LT, Danielsen TK, Hall V et al (2012) Antimicrobial susceptibility testing of Clostridium difficile using EUCAST epidemiological cut-off values and disk diffusion correlates. Clin Microbiol Infect 18:E266–E272PubMedCrossRefGoogle Scholar
  45. European Centre for Disease Prevention and Control (ECDC) (2013) Point prevalence survey of health care associated infections and antimicrobial use in European acute care hospitalsGoogle Scholar
  46. Falagas ME, Makris GC, Dimopoulos G et al (2008) Heteroresistance: a concern of increasing clinical significance? Clin Microbiol Infect 14:101–104PubMedCrossRefGoogle Scholar
  47. Farrow KA, Lyras D, Rood JI (2001) Genomic analysis of the erythromycin resistance element Tn5398 from Clostridium difficile. Microbiology 147:2717–2728PubMedCrossRefGoogle Scholar
  48. Fraga EG, Nicodemo AC, Sampaio JL (2016) Antimicrobial susceptibility of Brazilian Clostridium difficile strains determined by agar dilution and disk. Braz J Infect Dis 20:476–481PubMedCrossRefGoogle Scholar
  49. Freeman J, Stott J, Baines SD et al (2005) Surveillance for resistance to metronidazole and vancomycin in genotypically distinct and UK epidemic Clostridium difficile isolates in a large teaching hospital. J Antimicrob Chemother 56:988–989PubMedCrossRefGoogle Scholar
  50. Freeman J, Vernon J, Morris K et al (2015a) Pan-European longitudinal surveillance of antibiotic resistance among prevalent Clostridium difficile ribotypes. Clin Microbiol Infect 21:248.e9–248.e16CrossRefGoogle Scholar
  51. Freeman J, Vernon J, Vickers R et al (2015b) Susceptibility of Clostridium difficile isolates of varying antimicrobial resistance phenotypes to SMT19969 and 11 comparators. Antimicrob Agents Chemother 60:689–692PubMedPubMedCentralCrossRefGoogle Scholar
  52. Fry PR, Thakur S, Abley M et al (2012) Antimicrobial resistance, toxinotype, and genotypic profiling of Clostridium difficile isolates of swine origin. J Clin Microbiol 50:2366–2372PubMedPubMedCentralCrossRefGoogle Scholar
  53. Gal M, Brazier JS (2004) Metronidazole resistance in Bacteroides spp. carrying nim genes and the selection of slow-growing metronidazole-resistant mutants. J Antimicrob Chemother 54:109–116PubMedCrossRefGoogle Scholar
  54. Gao Q, Wu S, Huang H, Ni Y et al (2016) Toxin profiles, PCR ribotypes and resistance patterns of Clostridium difficile: a multicentre study in China, 2012–2013. Int J Antimicrob Agents 48:736–739PubMedCrossRefGoogle Scholar
  55. Genzel GH, Stubbings W, Stingu CS et al (2014) Activity of the investigational fluoroquinolone finafloxacin and seven other antimicrobial agents against 114 obligately anaerobic bacteria. Int J Antimicrob Agents 44:420–423PubMedCrossRefGoogle Scholar
  56. Goh S, Hussain H, Chang BJ et al (2013) Phage ϕC2 mediates transduction of Tn6215, encoding erythromycin resistance, between Clostridium difficile strains. MBio 4:e00840–e00813PubMedPubMedCentralCrossRefGoogle Scholar
  57. Goldman P (1982) The development of 5-nitroimidazoles for the treatment and prophylaxis of anaerobic bacterial infections. J Antimicrob Chemother 10(Suppl. A):23–33PubMedCrossRefGoogle Scholar
  58. Goldstein EJ, Citron DM, Sears P et al (2011) Comparative susceptibilities of fidaxomicin (OPT-80) of isolates collected at baseline, recurrence, and failure from patients in two fidaxomicin phase III trials of C. difficile infection. Antimicrob Agents Chemother 55:5194–5199PubMedPubMedCentralCrossRefGoogle Scholar
  59. Goldstein EJ, Babakhani F, Citron DM (2012) Antimicrobial activities of fidaxomicin. Clin Infect Dis 55(Suppl. 2):S143–S148PubMedPubMedCentralCrossRefGoogle Scholar
  60. Goorhuis A, Van der Kooi T, Vaessen N et al (2007) Spread and epidemiology of Clostridium difficile polymerase chain reaction ribotype 027/toxinotype III in The Netherlands. Clin Infect Dis 45:695–703PubMedCrossRefGoogle Scholar
  61. Goudarzi M, Goudarzi H, Alebouyeh M et al (2013) Antimicrobial susceptibility of Clostridium difficile clinical isolates in Iran. Iran Red Crescent Med J 15:704–711PubMedPubMedCentralCrossRefGoogle Scholar
  62. Gravel D, Miller M, Simor A, Taylor G et al (2009) Canadian Nosocomial Infection Surveillance Program. Health care-associated Clostridium difficile infection in adults admitted to acute care hospitals in Canada: a Canadian Nosocomial Infection Surveillance Program study. Clin Infect Dis 48:568–576PubMedCrossRefGoogle Scholar
  63. Hächler H, Berger-Bächi B, Kayser FH (1987) Genetic characterization of a Clostridium difficile erythromycin-clindamycin resistance determinant that is transferable to Staphylococcus aureus. Antimicrob Agents Chemother 7:1039–1045CrossRefGoogle Scholar
  64. Hansen LH, Vester B (2015) A cfr-like gene from Clostridium difficile confers multiple antibiotic resistance by the same mechanism as the cfr gene. Antimicrob Agents Chemother 59:5841–5843PubMedPubMedCentralCrossRefGoogle Scholar
  65. Hastey CJ, Dale SE, Nary J et al (2017) Comparison of Clostridium difficile minimum inhibitory concentrations obtained using agar dilution vs broth microdilution methods. Anaerobe 44:73–77PubMedCrossRefGoogle Scholar
  66. He M, Sebaihia M, Lawley TD et al (2010) Evolutionary dynamics of Clostridium difficile over short and long time scales. PNAS 107:7527–7532PubMedPubMedCentralCrossRefGoogle Scholar
  67. He M, Miyajima F, Roberts P, Ellison L et al (2013) Emergence and global spread of epidemic healthcare-associated Clostridium difficile. Nat Genet 45:109–113PubMedPubMedCentralCrossRefGoogle Scholar
  68. Holt HM, Danielsen TK, Justesen US (2015) Routine disc diffusion antimicrobial susceptibility testing of Clostridium difficile and association with PCR ribotype 027. Eur J Clin Microbiol Infect Dis 34:2243–2246PubMedCrossRefGoogle Scholar
  69. Huang H, Weintraub A, Fang H et al (2009) Antimicrobial resistance in Clostridium difficile. Int J Antimicrob Agents 34:516–522PubMedCrossRefGoogle Scholar
  70. Huang JS, Jiang Z-D, Garey KW et al (2013) Use of rifamycin drugs and development of infection by rifamycin-resistant strains of Clostridium difficile. Antimicrob Agents Chemother 57:2690–2693PubMedPubMedCentralCrossRefGoogle Scholar
  71. Impallomeni M, Galletly NP, Wort J et al (1995) Increased risk of diarrhoea caused by Clostridium difficile in elderly patients receiving cefotaxime. BMJ 311:1345–1346PubMedPubMedCentralCrossRefGoogle Scholar
  72. Iv ECO, Iii ECO, Johnson DA (2014) Clinical update for the diagnosis and treatment of Clostridium difficile infection. World J Gastrointest Pharmacol Ther 5:1–26PubMedPubMedCentralCrossRefGoogle Scholar
  73. Jamal WY, Rotimi VO (2016) Surveillance of antibiotic resistance among hospital- and community-acquired toxigenic Clostridium difficile isolates over 5-year period in Kuwait. PLoS One 11:e0161411PubMedPubMedCentralCrossRefGoogle Scholar
  74. Jarrad AM, Karoli T, Blaskovich MAT et al (2015) Clostridium difficile drug pipeline: challenges in discovery and development of new agents. J Med Chem 58:5164–5185PubMedPubMedCentralCrossRefGoogle Scholar
  75. Jasni AS, Mullany P, Hussain H et al (2010) Demonstration of conjugative transposon (Tn5397)-mediated horizontal gene transfer between Clostridium difficile and Enterococcus faecalis. Antimicrob Agents Chemother 54:4924–4926PubMedPubMedCentralCrossRefGoogle Scholar
  76. Johnson S, Schriever C, Patel U et al (2009) Rifaximin redux: treatment of recurrent Clostridium difficile infections with rifaximin immediately post-vancomycin treatment. Anaerobe 15:290–291PubMedCrossRefGoogle Scholar
  77. Karlowsky JA, Zhanel GG, Hammond GW et al (2012) Multidrug-resistant North American pulsotype 2 Clostridium difficile was the predominant toxigenic hospital-acquired strain in the province of Manitoba, Canada, in 2006–2007. J Med Microbiol 61:693–700PubMedCrossRefGoogle Scholar
  78. Khan R, Cheesbrough J (2003) Impact of changes in antibiotic policy on Clostridium difficile-associated diarrhoea (CDAD) over a five-year period in a district general hospital. J Hosp Infect 54:104–108PubMedCrossRefGoogle Scholar
  79. Kim J, Kang JO, Pai H et al (2012) Association between PCR ribotypes and antimicrobial susceptibility among Clostridium difficile isolates from healthcare-associated infections in South Korea. Int J Antimicrob Agents 40:24–29PubMedCrossRefGoogle Scholar
  80. Knight DR, Riley TV (2016) Clostridium difficile clade 5 in Australia: antimicrobial susceptibility profiling of PCR ribotypes of human and animal origin. J Antimicrob Chemother 71:2213–2217PubMedCrossRefGoogle Scholar
  81. Knight DR, Giglio S, Huntington PG et al (2015) Surveillance for antimicrobial resistance in Australian isolates of Clostridium difficile, 2013–2014. J Antimicrob Chemother 70:2992–2999PubMedCrossRefGoogle Scholar
  82. Kociolek LK, Gerding DN, Osmolski JR et al (2016) Differences in the molecular epidemiology and antibiotic susceptibility of Clostridium difficile isolates in pediatric and adult patients. Antimicrob Agents Chemother 60:4896–4900PubMedPubMedCentralCrossRefGoogle Scholar
  83. Kouzegaran S, Ganjifard M, Tanha AS (2016) Detection, ribotyping and antimicrobial resistance properties of Clostridium difficile strains isolated from the cases of diarrhea. Mater Sociomed 28:324–328PubMedPubMedCentralCrossRefGoogle Scholar
  84. Krutova M, Matejkova J, Tkadlec J et al (2015) Antibiotic profiling of Clostridium difficile ribotype 176 – a multidrug resistant relative to C. difficile ribotype 027. Anaerobe 36:88–90CrossRefPubMedGoogle Scholar
  85. Kullin B, Brock T, Rajabally N et al (2016) Characterizations of Clostridium difficile strains isolated from Groote Schuur Hospital, Cape Town, South Africa. Eur J Clin Microbiol Infect Dis 35:1709–1718PubMedCrossRefGoogle Scholar
  86. Kullin B, Wojno J, Abratt V et al (2017) Toxin A-negative toxin B-positive ribotype 017 Clostridium difficile is the dominant strain type in patients with diarrhoea attending tuberculosis hospitals in Cape Town, South Africa. Eur J Clin Microbiol Infect Dis 36:163–175PubMedCrossRefGoogle Scholar
  87. Kuwata Y, Tanimoto S, Sawabe E et al (2015) Molecular epidemiology and antimicrobial susceptibility of Clostridium difficile isolated from a university teaching hospital in Japan. Eur J Clin Microbiol Infect 34:763–772CrossRefGoogle Scholar
  88. Lachowicz D, Pituch H, Obuch-Woszczatyński P (2015) Antimicrobial susceptibility patterns of Clostridium difficile strains belonging to different polymerase chain reaction ribotypes isolated in Poland in 2012. Anaerobe 31:37–41PubMedCrossRefGoogle Scholar
  89. Lee J-H, Lee Y, Lee K et al (2014) The changes of PCR ribotype and antimicrobial resistance of Clostridium difficile in a tertiary care hospital over 10 years. J Med Microbiol 63:819–823PubMedCrossRefGoogle Scholar
  90. Leeds JA, Sachdeva M, Mullin S et al (2014) In vitro selection, via serial passage, of Clostridium difficile mutants with reduced susceptibility to fidaxomicin or vancomycin. J Antimicrob Chemother 69:41–44PubMedCrossRefGoogle Scholar
  91. Lessa FC, Gould CV, McDonald LC (2012) Current status of Clostridium difficile infection epidemiology. Clin Infect Dis 55:65–70CrossRefGoogle Scholar
  92. Lessa FC, Mu Y, Bamberg WM et al (2015) Burden of Clostridium difficile infection in the United States. N Engl J Med 372:825–834CrossRefPubMedGoogle Scholar
  93. Liao CH, Ko WC, Lu JJ et al (2012) Characterizations of clinical isolates of Clostridium difficile by toxin genotypes and by susceptibility to 12 antimicrobial agents, including fidaxomicin (OPT-80) and rifaximin: a multicenter study in Taiwan. Antimicrob Agents Chemother 56:3943–3949PubMedPubMedCentralCrossRefGoogle Scholar
  94. Lim SC, Foster NF, Riley TV (2016) Susceptibility of Clostridium difficile to the food preservatives sodium nitrite, sodium nitrate and sodium metabisulphite. Anaerobe 37:67–71PubMedCrossRefGoogle Scholar
  95. López-Ureña D, Quesada-Gómez C, Montoya-Ramírez M et al (2016) Predominance and high antibiotic resistance of the emerging Clostridium difficile genotypes NAPCR1 and NAP9 in a Costa Rican hospital over a 2-year period without outbreaks. Emerg Microbes Infect 5:e42PubMedPubMedCentralCrossRefGoogle Scholar
  96. Louie TJ, Miller MA, Mullane KM et al (2011) Fidaxomicin versus Vancomycin for Clostridium difficile infection. N Engl J Med 364:422–431PubMedPubMedCentralCrossRefGoogle Scholar
  97. Louie TJ, Cannon K, Byrne B et al (2012) Fidaxomicin preserves the intestinal microbiome during and after treatment of Clostridium difficile infection (CDI) and reduces both toxin reexpression and recurrence of CDI. Clin Infect Dis 55(Suppl. 2):S132–S142PubMedPubMedCentralCrossRefGoogle Scholar
  98. Lynch T, Chong P, Zhang J et al (2013) Characterization of a stable, metronidazole-resistant Clostridium difficile clinical isolate. PLoS One 8:e53757PubMedPubMedCentralCrossRefGoogle Scholar
  99. Lyras D, Cooper MA (2015) Clostridium difficile drug pipeline: challenges in discovery and development of new agents. J Med Chem 58:5164–5185PubMedPubMedCentralCrossRefGoogle Scholar
  100. Lyras D, Storie C, Huggins AS et al (1998) Chloramphenicol resistance in Clostridium difficile is encoded on Tn4453 transposons that are closely related to Tn4451 from Clostridium perfringens. Antimicrob Agents Chemother 42:1563–1156PubMedPubMedCentralGoogle Scholar
  101. Mac Aogáin M, Kilkenny S, Walsh C et al (2015) Identification of a novel mutation at the primary dimer interface of GyrA conferring fluoroquinolone resistance in Clostridium difficile. J Glob Antimicrob Resist 3:295–299PubMedCrossRefGoogle Scholar
  102. Mackin KE, Elliott B, Kotsanas D et al (2015) Molecular characterization and antimicrobial susceptibilities of Clostridium difficile clinical isolates from Victoria, Australia. Anaerobe 34:80–83PubMedCrossRefGoogle Scholar
  103. Marin M, Martin A, Alcala L et al (2015) Clostridium difficile isolates with high linezolid MICs harbor the multiresistance gene cfr. Antimicrob Agents Chemother 59:586–589PubMedCrossRefGoogle Scholar
  104. McDonald LC, Killgore GE, Thompson A et al (2005) An epidemic, toxin gene–variant strain of Clostridium difficile. N Engl J Med 353:2433–2441PubMedPubMedCentralCrossRefGoogle Scholar
  105. Miller BA, Chen LF, Sexton DJ et al (2011a) Comparison of the burdens of hospital-onset, healthcare facility-associated Clostridium difficile infection and of healthcare-associated infection due to methicillin-resistant Staphylococcus aureus in community hospitals. Infect Control Hosp Epidemiol 32:387–390PubMedCrossRefGoogle Scholar
  106. Miller MA, Blanchette R, Spigaglia P et al (2011b) Divergent rifamycin susceptibilities of Clostridium difficile strains in Canada and Italy and predictive accuracy of rifampin Etest for rifamycin resistance. J Clin Microbiol 49:4319–4321PubMedPubMedCentralCrossRefGoogle Scholar
  107. Miller-Roll T, Na’amnih W, Cohen D et al (2016) Molecular types and antimicrobial susceptibility patterns of Clostridium difficile isolates in different epidemiological settings in a tertiary care center in Israel. Diagn Microbiol Infect Dis 86:450–454PubMedCrossRefGoogle Scholar
  108. Moura I, Spigaglia P, Barbanti F et al (2013) Analysis of metronidazole susceptibility in different Clostridium difficile PCR ribotypes. J Antimicrob Chemother 68:362–365PubMedPubMedCentralCrossRefGoogle Scholar
  109. Moura I, Monot M, Tani C et al (2014) Multidisciplinary analysis of a nontoxigenic Clostridium difficile strain with stable resistance to metronidazole. Antimicrob Agents Chemother 58:4957–4960PubMedPubMedCentralCrossRefGoogle Scholar
  110. Mullane KM, Gorbach S (2011) Fidaxomicin: first-in-class macrocyclic antibiotic. Expert Rev Anti-Infect Ther 9:767–777PubMedCrossRefGoogle Scholar
  111. Mullany P, Wilks M, Lamb I et al (1990) Genetic analysis of a tetracycline resistance determinant from Clostridium difficile and its conjugal transfer to and from Bacillus subtilis. J Gen Microbiol 136:1343–1349PubMedCrossRefGoogle Scholar
  112. Mullany P, Wilks M, Tabaqchali S (1995) Transfer of macrolide-lincosamide-streptogramin B (MLS) resistance in Clostridium difficile is linked to a gene homologous with toxin A and is mediated by a conjugative transposon, Tn5398. J Antimicrob Chemother 2:305–315CrossRefGoogle Scholar
  113. Mullany P, Williams R, Langridge GC et al (2012) Behavior and target site selection of conjugative transposon Tn916 in two different strains of toxigenic Clostridium difficile. Appl Environ Microbiol 78:2147–2153PubMedPubMedCentralCrossRefGoogle Scholar
  114. Mullany P, Allan E, Roberts AP (2015) Mobile genetic elements in Clostridium difficile and their role in genome function. Res Microbiol 166:361–367PubMedPubMedCentralCrossRefGoogle Scholar
  115. Musher DM, Aslam S, Logan N et al (2005) Relatively poor outcome after treatment of Clostridium difficile colitis with metronidazole. Clin Infect Dis 40:1586–1590PubMedCrossRefGoogle Scholar
  116. Muto CA, Pokrywka M, Shutt K et al (2005) A large outbreak of Clostridium difficile-associated disease with an unexpected proportion of deaths and colectomies at a teaching hospital following increased fluoroquinolone use. Infect Control Hosp Epidemiol 26:273–280PubMedCrossRefGoogle Scholar
  117. Muto CA, Blank MK, Marsh JW et al (2007) Control of an outbreak of infection with the hypervirulent Clostridium difficile BI strain in a university hospital using a comprehensive “bundle” approach. Clin Infect Dis 45:1266–1273PubMedCrossRefGoogle Scholar
  118. Norman KN, Scott HM, Harvey RB et al (2014) Comparison of antimicrobial susceptibility among Clostridium difficile isolated from an integrated human and swine population in Texas. Foodborne Pathog Dis 11:257–264PubMedCrossRefGoogle Scholar
  119. Novak A, Spigaglia P, Barbanti F et al (2014) First clinical and microbiological characterization of Clostridium difficile infection in a Croatian University Hospital. Anaerobe 30:18–23PubMedCrossRefGoogle Scholar
  120. Nyc O, Tejkalova R, Kriz Z et al (2017) Two clusters of fluoroquinolone and clindamycin-resistant Clostridium difficile PCR ribotype 001 strain recognized by capillary electrophoresis ribotyping and multilocus variable tandem repeat analysis. Microb Drug Resist 23:609–615PubMedCrossRefGoogle Scholar
  121. O’Connor JR, Galang MA, Sambol SP et al (2008) Rifampin and rifaximin resistance in clinical isolates of Clostridium difficile. Antimicrob Agents Chemother 52:2813–2817PubMedPubMedCentralCrossRefGoogle Scholar
  122. Obuch-Woszczatyński P, Dubiel G, Harmanus C et al (2013) Emergence of Clostridium difficile infection in tuberculosis patients due to a highly rifampicin-resistant PCR ribotype 046 clone in Poland. Eur J Clin Microbiol Infect Dis 32:1027–1103PubMedPubMedCentralCrossRefGoogle Scholar
  123. Obuch-Woszczatyński P, Lachowicz D, Schneider A et al (2014) Occurrence of Clostridium difficile PCR-ribotype 027 and it’s closely related PCR-ribotype 176 in hospitals in Poland in 2008–2010. Anaerobe 28:13–17CrossRefPubMedGoogle Scholar
  124. Oka K, Osaki T, Hanawa T et al (2012) Molecular and microbiological characterization of Clostridium difficile isolates from single, pelapse, and reinfection cases. J Clin Microbiol 50:915–921PubMedPubMedCentralCrossRefGoogle Scholar
  125. Optimer Pharmaceuticals, Inc. (2011) Anti-infective drugs advisory committee briefing document: dificid™ (fidaxomicin tablets) for the treatment of Clostridium difficile infection (CDI), also known as Clostridium difficile-associated diarrhea (CDAD), and for reducing the risk of recurrence when used for treatment of initial CDI. Available at: MeetingMaterials/Drugs/Anti-InfectiveDrugsAdviso ryCommittee/UCM249354.pdf
  126. Pecavar V, Blaschitz M, Hufnagl P et al (2012) High-resolution melting analysis of the single nucleotide polymorphism hot-spot region in the rpoB gene as an indicator of reduced susceptibility to rifaximin in Clostridium difficile. J Med Microbiol 61:780–785PubMedCrossRefGoogle Scholar
  127. Peláez T, Cercenado E, Alcalá L et al (2008) Metronidazole resistance in Clostridium difficile is heterogeneous. J Clin Microbiol 46:3028–3032PubMedPubMedCentralCrossRefGoogle Scholar
  128. Pépin JL, Valiquette ME, Alary ME et al (2004) Clostridium difficile-associated diarrhea in a region of Quebec from 1991–2003: a changing pattern disease severity. CMAJ 17:466–472CrossRefGoogle Scholar
  129. Pépin J, Alary ME, Valiquette L et al (2005a) Increasing risk of relapse after treatment of Clostridium difficile colitis in Quebec, Canada. Clin Infect Dis 40:1591–1597PubMedCrossRefGoogle Scholar
  130. Pépin JL, Valiquette ME, Clossette B (2005b) Mortality attributed to nosocomial Clostridium difficile-associated disease during an epidemic caused by a hyperviluent strain in Quebec. CMAJ 173:1037–1042PubMedPubMedCentralCrossRefGoogle Scholar
  131. Perkins HR, Nieto M (1974) The chemical basis for the action of the vancomycin group of antibiotics. Ann N Y Acad Sci 235:348–363PubMedCrossRefGoogle Scholar
  132. Pirš T, Avberšek J, Zdovc I et al (2013) Antimicrobial susceptibility of animal and human isolates of Clostridium difficile by broth microdilution. J Med Microbiol 62:1478–1485PubMedCrossRefGoogle Scholar
  133. Pituch H, Brazier JS, Obuch-Woszczatynski P et al (2006) Prevalence and association of PCR ribotypes of Clostridium difficile isolated from symptomatic patients from Warsaw with macrolide-lincosamide-streptogramin B (MLSB) type resistance. J Med Microbiol 55:207–213PubMedCrossRefGoogle Scholar
  134. Poilane I, Cruaud P, Torlotin JC et al (2000) Comparison of the E test to the reference agar dilution method for antibiotic susceptibility testing of Clostridium difficile. Clin Microbiol Infect 6:155–156PubMedCrossRefGoogle Scholar
  135. Putsathit P, Maneerattanaporn M, Piewngam P et al (2017) Antimicrobial susceptibility of Clostridium difficile isolated in Thailand. Antimicrob Resist Infect Control 6:58. Scholar
  136. Ramírez-Vargas G, Quesada-Gómez C, Acuña-Amador L et al (2017) A Clostridium difficile lineage endemic to Costa Rican hospitals is multidrug resistant by acquisition of chromosomal mutations and novel mobile genetic elements. Antimicrob Agents Chemother 61:e02054. Scholar
  137. Ratnayake L, McEwen J, Henderson N et al (2011) Control of an outbreak of diarrhoea in a vascular surgery unit caused by a high-level clindamycin-resistant Clostridium difficile PCR ribotype 106. J Hosp Infect 79:242–247PubMedCrossRefGoogle Scholar
  138. Redelings MD, Sorvillo F, Mascola L (2007) Increase in Clostridium difficile-related mortality rates, United States, 1999–2004. Emerg Infect Dis 13:1417–1419PubMedPubMedCentralCrossRefGoogle Scholar
  139. Reil M, Hensgens MPM, Kuijper EJ et al (2012) Seasonality of Clostridium difficile infections in Southern Germany. Epidemiol Infect 140:1787–1793PubMedCrossRefGoogle Scholar
  140. Richardson C, Kim P, Lee C et al (2015) Comparison of Clostridium difficile isolates from individuals with recurrent and single episode of infection. Anaerobe 33:105–108PubMedCrossRefGoogle Scholar
  141. Roberts AP, Mullany P (2011) Tn916-like genetic elements: a diverse group of modular mobile elements conferring antibiotic resistance. FEMS Microbiol Rev 35:856–871PubMedCrossRefGoogle Scholar
  142. Roberts MC, McFarland LV, Mullany P et al (1994) Characterization of the genetic basis of antibiotic resistance in Clostridium difficile. J Antimicrob Chemother 33:419–429PubMedCrossRefGoogle Scholar
  143. Roberts AP, Johanesen PA, Lyras D et al (2001) Comparison of Tn5397 from Clostridium difficile, Tn916 from Enterococcus faecalis and the CW459tet(M) element from Clostridium perfringens shows that they have similar conjugation regions but different insertion and excision modules. Microbiology 147:1243–1251PubMedCrossRefGoogle Scholar
  144. Rodríguez-Pardo D, Almirante B, Bartolomé RM et al (2013) Epidemiology of Clostridium difficile infection and risk factors for unfavorable clinical outcomes: results of a hospital-based study in Barcelona, Spain. J Clin Microbiol 51:1465–1473PubMedPubMedCentralCrossRefGoogle Scholar
  145. Salix Pharmaceuticals, Ltd. 10 December 2003, posting date. Salix receives FDA notification that rifaximin amendment considered a complete response. Salix Pharmaceuticals, Raleigh.
  146. Santos A, Isidro J, Silva C et al (2016) Molecular and epidemiologic study of Clostridium difficile reveals unusual heterogeneity in clinical strains circulating in different regions in Portugal. Clin Microbiol Infect 22:695–700CrossRefPubMedGoogle Scholar
  147. Schmidt C, Löffler B, Ackermann G (2007) Antimicrobial phenotypes and molecular basis in clinical strains of Clostridium difficile. Diagn Microbiol Infect Dis 59:1–5PubMedCrossRefGoogle Scholar
  148. Sears P, Crook DW, Louie TJ et al (2012) Fidaxomicin attains high fecal concentrations with minimal plasma concentrations following oral administration in patients with Clostridium difficile infection. Clin Infect Dis 55(Suppl 2):S116–SS12PubMedPubMedCentralCrossRefGoogle Scholar
  149. Sebaihia M, Wren BW, Mullany P et al (2006) The multidrug-resistant human pathogen Clostridium difficile has a highly mobile, mosaic genome. Nat Genet 38:779–786PubMedPubMedCentralCrossRefGoogle Scholar
  150. Senoh M, Kato H, Fukuda T et al (2015) Predominance of PCR-ribotypes, 018 (smz) and 369 (trf) of Clostridium difficile in Japan: a potential relationship with other global circulating strains? J Med Microbiol 64:1226–1236PubMedCrossRefGoogle Scholar
  151. Seugendo M, Mshana SE, Hokororo A et al (2015) Clostridium difficile infections among adults and children in Mwanza/Tanzania: is it an underappreciated pathogen among immunocompromised patients in sub-Saharan Africa? New Microbes New Infect 8:99–102PubMedPubMedCentralCrossRefGoogle Scholar
  152. Shayganmehr F-S, Alebouyeh M, Azimirad M et al (2015) Association of tcdA+/tc dB+ Clostridium difficile genotype with emergence of multidrugresistant strains conferring metronidazole resistant phenotype. Iran Biomed J 19:143–148PubMedPubMedCentralGoogle Scholar
  153. Simango C, Uladi S (2014) Detection of Clostridium difficile diarrhoea in Harare, Zimbabwe. Trans R Soc Trop Med Hyg 108:354–357PubMedCrossRefGoogle Scholar
  154. Spigaglia P (2016) Recent advances in the understanding of antibiotic resistance in Clostridium difficile infection. Ther Adv Infect Dis 3:23–42PubMedPubMedCentralCrossRefGoogle Scholar
  155. Spigaglia P, Mastrantonio P (2004) Comparative analysis of Clostridium difficile clinical isolates belonging to different genetic lineages and time periods. J Med Microbiol 53:1129–1136PubMedCrossRefGoogle Scholar
  156. Spigaglia P, Carucci V, Barbanti F et al (2005) ErmB determinants and Tn916-like elements in clinical isolates of Clostridium difficile. Antimicrob Agents Chemother 49:2550–2553PubMedPubMedCentralCrossRefGoogle Scholar
  157. Spigaglia P, Barbanti F, Mastrantonio P (2006) New variants of the tet(M) gene in Clostridium difficile clinical isolates harbouring Tn916-like elements. J Antimicrob Chemother 57:1205–1209PubMedCrossRefGoogle Scholar
  158. Spigaglia P, Barbanti F, Mastrantonio P (2007) Detection of a genetic linkage between genes coding for resistance to tetracycline and erythromycin in Clostridium difficile. Microb Drug Resist 13:90–95PubMedCrossRefGoogle Scholar
  159. Spigaglia P, Barbanti F, Mastrantonio P (2008a) Tetracycline resistance gene tet(W) in the pathogenic bacterium Clostridium difficile. Antimicrob Agents Chemother 52:770–773PubMedCrossRefGoogle Scholar
  160. Spigaglia P, Barbanti F, Mastrantonio P et al (2008b) Fluoroquinolone resistance in Clostridium difficile isolates from a prospective study of C. difficile infections in Europe. J Med Microbiol 57:784–789PubMedCrossRefGoogle Scholar
  161. Spigaglia P, Barbanti F, Louie T et al (2009) Molecular analysis of the gyrA and gyrB quinolone resistance-determining regions of fluoroquinolone-resistant Clostridium difficile mutants selected in vitro. Antimicrob Agents Chemother 53:2463–2468PubMedPubMedCentralCrossRefGoogle Scholar
  162. Spigaglia P, Barbanti F, Dionisi AM et al (2010) Clostridium difficile isolates resistant to fluoroquinolones in Italy: emergence of PCR ribotype 018. J Clin Microbiol 48:2892–2896PubMedPubMedCentralCrossRefGoogle Scholar
  163. Spigaglia P, Barbanti F, Mastrantonio P, European Study Group on Clostridium difficile (ESGCD) (2011) Multidrug resistance in European Clostridium difficile clinical isolates. J Antimicrob Chemother 66:2227–2234PubMedPubMedCentralCrossRefGoogle Scholar
  164. Spigaglia P, Barbanti F, Morandi M et al (2015) Diagnostic testing for Clostridium difficile in Italian microbiological laboratories. Anaerobe 37:29–33PubMedCrossRefGoogle Scholar
  165. Srivastava A, Talaue M, Liu S et al (2011) New target for inhibition of bacterial RNA polymerase: “switch region”. Curr Opin Microbiol Antimicrob/Genomics 14:532–543CrossRefGoogle Scholar
  166. Tannock GW, Munro K, Taylor C et al (2010) A new macrocyclic antibiotic, fidaxomicin (OPT-80), causes less alteration to the bowel microbiota of Clostridium difficile-infected patients than does vancomycin. Microbiology 156:3354–3359PubMedCrossRefGoogle Scholar
  167. Tenover FC, Tickler IA, Persing DH (2012) Antimicrobial-resistant strains of Clostridium difficile from North America. Antimicrob Agents Chemother 56:2929–2932PubMedPubMedCentralCrossRefGoogle Scholar
  168. Terhes G, Maruyama A, Latkóczy K et al (2014) In vitro antibiotic susceptibility profile of Clostridium difficile excluding PCR ribotype 027 outbreak strain in Hungary. Anaerobe 30:41–44PubMedCrossRefGoogle Scholar
  169. Vardakas KZ, Polyzos KA, Patouni K et al (2012) Treatment failure and recurrence of Clostridium difficile infection following treatment with vancomycin or metronidazole: a systematic review of the evidence. Int J Antimicrob Agents 40:1–8CrossRefPubMedGoogle Scholar
  170. Varshney JB, Very KJ, Williams JL et al (2014) Characterization of Clostridium difficile isolates from human fecal samples and retail meat from Pennsylvania. Foodborne Pathog Dis 11:822–829PubMedCrossRefGoogle Scholar
  171. Vuotto C, Moura I, Barbanti F et al (2016) Subinhibitory concentrations of metronidazole increase biofilm formation in Clostridium difficile strains. Pathog Dis 74:ftv114. Scholar
  172. Walkty A, Boyd DA, Gravel D et al (2010) Molecular characterization of moxifloxacin resistance from Canadian Clostridium difficile clinical isolates. Diagn Microbiol Infect Dis 66:419–424PubMedCrossRefGoogle Scholar
  173. Wang H, Smith MCM, Mullany P (2006) The conjugative transposon Tn5397 has a strong preference for integration into its Clostridium difficile target site. J Bacteriol 188:4871–4878PubMedPubMedCentralCrossRefGoogle Scholar
  174. Wasels F, Spigaglia P, Barbanti F et al (2013) Clostridium difficile erm(B)-containing elements and the burden on the in vitro fitness. J Med Microbiol 62:1461–1467PubMedCrossRefGoogle Scholar
  175. Wasels F, Monot M, Spigaglia P et al (2014) Inter- and intraspecies transfer of a Clostridium difficile conjugative transposon conferring resistance to MLSB. Microb Drug Resist 20:555–560PubMedCrossRefGoogle Scholar
  176. Wasels F, Kuehne SA, Cartman ST et al (2015a) Fluoroquinolone resistance does not impose a cost on the fitness of Clostridium difficile in vitro. Antimicrob Agents Chemother 59:1794–1796PubMedPubMedCentralCrossRefGoogle Scholar
  177. Wasels F, Spigaglia P, Barbanti F et al (2015b) Integration of erm(B)-containing elements through large chromosome fragment exchange in Clostridium difficile. Mob Genet Elem 1:12–16CrossRefGoogle Scholar
  178. Weber I, Riera E, Déniz C et al (2013) Molecular epidemiology and resistance profiles of Clostridium difficile in a tertiary care hospital in Spain. Int J Med Microbiol 303:128–133PubMedCrossRefGoogle Scholar
  179. Wiström J, Norrby SR, Myhre EB et al (2001) Frequency of antibiotic-associated diarrhea in 2462 antibiotic-treated hospitalized patients: a prospective study. J Antimicrob Chemother 47:43–50PubMedCrossRefGoogle Scholar
  180. Wren BW, Mullany P, Clayton C et al (1988) Molecular cloning and genetic analysis of a chloramphenicol acetyltransferase determinant from Clostridium difficile. Antimicrob Agents Chemother 32:1213–1121PubMedPubMedCentralCrossRefGoogle Scholar
  181. Wren BW, Mullany P, Clayton C et al (1989) Nucleotide sequence of a chloramphenicol acetyl transferase gene from Clostridium difficile. Nucleic Acids Res 17:4877PubMedPubMedCentralCrossRefGoogle Scholar
  182. Young GP, Ward PB, Bayley N et al (1985) Antibiotic-associated colitis due to Clostridium difficile: double-blind comparison of vancomycin with bacitracin. Gastroenterology 89:1038–1045PubMedCrossRefGoogle Scholar
  183. Yu X, Sun D (2013) Macrocyclic drugs and synthetic methodologies toward macrocycles. Molecules 18:6230–6268PubMedPubMedCentralCrossRefGoogle Scholar
  184. Zhou Y, Burnham C-AD, Hink T et al (2014) Phenotypic and genotypic analysis of Clostridium difficile isolates: a single-center study. J Clin Microbiol 52:4260–4266PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Patrizia Spigaglia
    • 1
    Email author
  • Paola Mastrantonio
    • 1
  • Fabrizio Barbanti
    • 1
  1. 1.Department of Infectious DiseasesIstituto Superiore di SanitàRomeItaly

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