Heteroresistance: A Harbinger of Future Resistance

  • Karl DrlicaEmail author
  • Bo Shopsin
  • Xilin Zhao
Part of the Emerging Infectious Diseases of the 21st Century book series (EIDC)


During infection, bacterial populations often contain subpopulations that exhibit reduced antimicrobial susceptibility. The resulting population heterogeneity is called heteroresistance. Since a heteroresistant population can evolve into a resistant one, a heteroresistant infection is a risk factor for the development of complete resistance. We describe heteroresistant tuberculosis as an example of a chronic infection in which enrichment of resistant subpopulations readily progresses in individual patients and threatens successful treatment. Heteroresistance provides such a clear warning that improved DNA-based tests are being designed to identify isolates containing resistant subpopulations while they are still small. We also examine heteroresistance with Staphylococcus aureus as an example of how resistant subpopulations affect treatment of an opportunistic pathogen. Heteroresistance to methicillin resistance emerged via a horizontal gene transfer event that produced methicillin-resistant S. aureus (MRSA), which spread worldwide. Now heteroresistance to vancomycin-intermediate Staphylococcus aureus (VISA) is appearing among MRSA strains. Many other pathogens are also displaying heteroresistance that is often undetected by routine, automated susceptibility testing. Refinement of assays is likely to reveal that antimicrobial heteroresistance is much more prevalent than we realize and that treatment strategies need to be refined now to slow the emergence of new resistance.



We thank the following for helpful discussions and critical comments: Veronique Dartois, Dorothy Fallows, Marila Gennaro, Ben Gold, Barry Kreiswirth, Richard Pine, and George Zhanel. The authors’ work was supported by NIH grants 1DP20D007423, 1R01AI073491, 1R21A03781, and 1R01AI87671.


  1. 1.
    Bush K, Fisher J. Epidemiological expansion, structural studies, and clinical challenges of new β-lactamases from gram-negative bacteria. Annu Rev Microbiol. 2011;65:455–78.PubMedGoogle Scholar
  2. 2.
    Chambers H, Deleo F. Waves of resistance: Staphylococcus aureus in the antibiotic era. Nat Rev Microbiol. 2009;7:629–41.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Drlica K, Zhao X. Mutant selection window hypothesis updated. Clin Inf Dis. 2007;44:681–8.Google Scholar
  4. 4.
    El-Halfawy O, Valvano M. Antimicrobial heteroresistance: an emerging field in need of clarity. Clin Microbiol Rev. 2015;28:191–207.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Liu C, Chambers H. Staphylococcus aureus with heterogeneous resistance to vancomycin: epidemiology, clinical significance, and critical assessment of diagnostic methods. Antimicrob Agents Chemother. 2003;47:3040–5.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Hiramatsu K, Cui L, Kuroda M, Ito T. The emergence and evolution of methicillin-resistant Staphylococcus aureus. Trends Microbiol. 2001;9:486–93.PubMedGoogle Scholar
  7. 7.
    Pournaras S, Ikonomidis A, Markogiannakis A, Maniatis A, Tsakris A. Heteroresistance to carbapenems in Acinetobacter baumannii. J Antimicrob Chemother. 2005;55(6):1055.PubMedGoogle Scholar
  8. 8.
    deLencastre H, SáFigueiredo A, Urban C, Rahal J, Tomasz A. Multiple mechanisms of methicillin resistance and improved methods for detection in clinical isolates of Staphylococcus aureus. Antimicrob Agents Chemother. 1991;35:632–9.Google Scholar
  9. 9.
    Dong Y, Zhao X, Domagala J, Drlica K. Effect of fluoroquinolone concentration on selection of resistant mutants of Mycobacterium bovis BCG and Staphylococcus aureus. Antimicrob Agents Chemother. 1999;43:1756–8.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Dong Y, Zhao X, Kreiswirth B, Drlica K. Mutant prevention concentration as a measure of antibiotic potency: studies with clinical isolates of Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2000;44:2581–4.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Ben-Ami R, Zimmerman O, Finn T, Amit S, Novikov A, Wertheimer N, et al. Heteroresistance to fluconazole is a continuously distributed phenotype among Candida glabrata clinical strains associated with in vivo persistence. MBio. 2016;7:pii: e00655–16.Google Scholar
  12. 12.
    Malik M, Hoatam G, Chavda K, Kerns R, Drlica K. Novel approach for comparing quinolones for emergence of resistant mutants during quinolone exposure. Antimicrob Agents Chemother. 2010;54:149–56.PubMedGoogle Scholar
  13. 13.
    Levin-Reisman I, Ronin I, Gefen O, Braniss I, Shoresh N, Balaban N. Antibiotic tolerance facilitates the evolution of resistance. Science. 2017;355:826–30.PubMedGoogle Scholar
  14. 14.
    Nicolas-Chanoine M, Bertrand X, Madec J. Escherichia coli ST131, an intriguing clonal group. Clin Microbiol Rev. 2014;27:543–74.PubMedPubMedCentralGoogle Scholar
  15. 15.
    East African Hospitals and British Medical Research Council. Comparative trial of isoniazid alone in low and high dosage and isoniazid plus PAS in the treatment of acute pulmonary tuberculosis in East Africa. Tubercle. 1960;40:83–102.Google Scholar
  16. 16.
    Crofton J, Mitchison D. Streptomycin resistance in pulmonary tuberculosis. Br Medical J. 1948;2:1009–15.Google Scholar
  17. 17.
    Canetti G, leLerzin M, Porven G, Rist N, Grumbach F. Some comparative apects of rifampicin and isoniazid. Tubercle. 1968;49:367–76.PubMedGoogle Scholar
  18. 18.
    Mitchison DA. Drug resistance in mycobacteria. Brit. Med Bull. 1984;40:84–90.Google Scholar
  19. 19.
    Canetti G. The J. Burns Amberson Lecture: present aspects of bacterial resistance in tuberculosis. Am Rev Resp Dis. 1965;92:687–703.PubMedGoogle Scholar
  20. 20.
    Lorian V, Finland M. In vitro effect of rifampicin on mycobacteria. App Microbiol. 1969;17:202–7.Google Scholar
  21. 21.
    Hobby G, Lenert T, Mater-Engallena J. In vitro activity of rifampin against the H37Rv strain of Mycobacterium tuberculosis. Am Rev Respir Dis. 1968;99:453–6.Google Scholar
  22. 22.
    Canetti G, Froman S, Grosset J, Hauduroy P, Langerová M, Mahler H, et al. Mycobacteria: laboratory methods for testing drug sensitivity and resistance. Bull World Health Organ. 1963;29:564–78.Google Scholar
  23. 23.
    McGrath M, GeyvanPittius N, vanHelden P, Warren R, Warner D. Mutation rate and the emergence of drug resistance in Mycobacterium tuberculosis. J Antimicrob Chemother. 2014;69:292–302.PubMedGoogle Scholar
  24. 24.
    Warner D, Ndwandwe D, Abrahams G, Kana B, Machowski E, Venclovas C, et al. Essential roles for imuA’- and imuB-encoded accessory factors in DnaE2-dependent mutagenesis in Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 2010;107:13093–8.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Fox W, Elklard G, Mitchison D. Studies on the treatment of tuberculosis undertaken by the British Medical Research Council Tuberculosis Units, 1946–1986, with relevant subsequent publications. Int J Tuberc Lung Dis. 1999;3:S231–S79.PubMedGoogle Scholar
  26. 26.
    Wayne LG, Hayes LG. An in vitro model for sequential study of shiftdown of Mycobacterium tuberculosis through two stages of nonreplicating persistence. Infect Immun. 1996;64:2062–9.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Kaplan G, Post F, Moreira A, Wainwright H, Kreiswirth B, Tanverdi M, et al. Mycobacterium tuberculosis growth at the cavity surface: a microenvironment with failed immunity. Infect Immun. 2003;71:7099–108.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Prideaux B, Via L, Zimmerman M, Eum S, Sarathy J, O'Brien P, et al. The association between sterilizing activity and drug distribution into tuberculosis lesions. Nat Med. 2015;21:1223–7.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Zetola N, Modongo C, Moonan P, Ncube R, Matlhagela K, Sepako E, et al. Clinical outcomes among persons with pulmonary tuberculosis caused by Mycobacterium tuberculosis isolates with phenotypic heterogeneity in results of drug-susceptibility tests. J Infect Dis. 2014;209:1754–63.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Cullen M, Sam N, Kanduma E, McHugh T, Gillespie S. Direct detection of heteroresistance in Mycobacterium tuberculosis using molecular techniques. J Med Microbiol. 2006;55(8):1157.PubMedGoogle Scholar
  31. 31.
    Plinke C, Cox H, Kalon S, Doshetov D, Rüsch-Gerdes S, Niemann S. Tuberculosis ethambutol resistance: concordance between phenotypic and genotypic test results. Tuberculosis. 2009;89:448–52.PubMedGoogle Scholar
  32. 32.
    Post F, Willcox P, Mathema B, Steyn L, Shean K, Ramaswamy S, et al. Genetic polymorphism in Mycobacterium tuberculosis isolates from patients with chronic multidrug-resistant tuberculosis. J Inf Dis. 2004;190:99–106.Google Scholar
  33. 33.
    Rinder H, Mieskes K, Loscher T. Heteroresistance in Mycobacterium tuberculosis. Int J Tuberc Lung Dis. 2001;5:339–45.PubMedGoogle Scholar
  34. 34.
    Hofmann-Thiel S, van Ingen J, Feldmann K, Turaev L, Uzakova G, Murmusaeva G, et al. Mechanisms of heteroresistance to isoniazid and rifampin of Mycobacterium tuberculosis in Tashkent, Uzbekistan. Eur Respir J. 2009;33:368–74.PubMedGoogle Scholar
  35. 35.
    Eilertson B, Maruri F, Blackman A, Herrera M, Samuels D, Sterling T. High proportion of heteroresistance in gyrA and gyrB in fluoroquinolone-resistant Mycobacterium tuberculosis clinical isolates. Antimicrob Agents Chemother. 2014;58:3270–5.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Zhang X, Zhao B, Huang H, Zhu Y, Peng J, Dai G, et al. Co-occurrence of amikacin-resistant and -susceptible Mycobacterium tuberculosis isolates in clinical samples from Beijing, China. J Antimicrob Chemother. 2013;68:1537–42.PubMedGoogle Scholar
  37. 37.
    Shamputa I, Rigouts L, Eyongeta L, El Aila N, van Deun A, Salim A, et al. Genotypic and phenotypic heterogeneity among Mycobacterium tuberculosis isolates from pulmonary tuberculosis patients. J Clin Microbiol. 2004;42:5528–36.PubMedPubMedCentralGoogle Scholar
  38. 38.
    van Rie A, Victor T, Richardson M, Johnson R, vanderSpuy G, Murray E, et al. Reinfection and mixed infection cause changing Mycobacterium tuberculosis drug-resistance patterns. Am J Respir Crit Care Med. 2005;172:636–42.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Blaas S, Mütterlein R, Weig J, Neher A, Salzberger B, Lehn N, et al. Extensively drug resistant tuberculosis in a high income country: a report of four unrelated cases. BMC Infect Dis. 2008;8:60.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Warren R, Victor T, Streicher E, Richardson M, Beyers N, GeyvanPittius N, et al. Patients with active tuberculosis often have different strains in the same sputum specimen. Am J Crit Care Med. 2004;169:610–4.Google Scholar
  41. 41.
    Meacci F, Orrù G, Iona E, Giannoni F, Piersimoni C, Pozzi G, et al. Drug resistance evolution of a Mycobacterium tuberculosis strain from a noncompliant patient. J Clin Microbiol. 2005;43:3114–20.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Xu C, Kreiswirth B, Sreevatsan S, Musser J, Drlica K. Fluoroquinolone resistance associated with specific gyrase mutations in clinical isolates of multidrug-resistant Mycobacterium tuberculosis. J. Inf. Dis. 1996;174:1127–30.PubMedGoogle Scholar
  43. 43.
    Shamputa I, Jugheli L, Sadradze N, Willery E, Portaels F, Supply P, et al. Mixed infection and clonal representativeness of a single sputum sample in tuberculosis patients from a penitentiary hospital in Georgia. Respir Res. 2006;7:99.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Vadwai V, Daver G, Udwadia Z, Sadani M, Shetty A, Rodrigues C. Clonal population of Mycobacterium tuberculosis strains reside within multiple lung cavities. PLoS One. 2011;6:e24770.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Lieberman T, Wilson D, Misra R, Xiong L, Moodley P, Cohen T, et al. Genomic diversity in autopsy samples reveals within-host dissemination of HIV-associated Mycobacterium tuberculosis. Nat Med. 2016;22:1470–4.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Behr M. Tuberculosis due to multiple strains: a concern for the patient? A concern for tuberculosis control? Am J Respir Crit Care Med. 2004;169(5):554.PubMedGoogle Scholar
  47. 47.
    Mankiewicz E, Liivak M. Phage types of Mycobacterium tuberculosis in cultures isolated from Eskimo patients. Am Rev Respir Dis. 1975;111:307–12.PubMedGoogle Scholar
  48. 48.
    Bates J, Stead W, Rado T. Phage type of tubercle bacilli isolated from patients with two or more sites of organ involvement. Am Rev Respir Dis. 1976;114:353–8.PubMedGoogle Scholar
  49. 49.
    Parsons L, Salfinger M, Clobridge A, Dormandy J, Mirabello L, Polletta V, et al. Phenotypic and molecular characterization of Mycobacterium tuberculosis isolates resistant to both isoniazid and ethambutol. Antimicrob Agents Chemother. 2005;49:2218–25.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Pholwat S, Stroup S, Foongladda S, Houpt E. Digital PCR to detect and quantify heteroresistance in drug resistant Mycobacterium tuberculosis. PLoS One. 2013;8:e57238.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Folkvardsen D, Svensson E, Thomsen V, Rasmussen E, Bang D, Werngren J, et al. Can molecular methods detect 1% isoniazid resistance in Mycobacterium tuberculosis? J Clin Microbiol. 2013a;51:1596–9.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Folkvardsen D, Thomsen V, Rigouts L, Rasmussen E, Bang D, Bernaerts G, et al. Rifampin heteroresistance in Mycobacterium tuberculosis cultures as detected by phenotypic and genotypic drug susceptibility test methods. J Clin Microbiol. 2013b;51:4220–2.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Hu S, Li G, Li H, Liu X, Niu J, Quan S, et al. Rapid detection of isoniazid resistance in Mycobacterium tuberculosis isolates by use of real-time-PCR-based melting curve analysis. J Clin Microbiol. 2014;52:1644–52.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Chakravorty S, Kothari H, Aladegbami B, Cho E, Lee J, Roh S, et al. Rapid, high-throughput detection of rifampin resistance and heteroresistance in Mycobacterium tuberculosis by use of sloppy molecular beacon melting temperature coding. J Clin Microbiol. 2012;50:2194–202.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Chakravorty S, Aladegbami B, Thoms K, Lee J, Lee E, Rajan V, et al. Rapid detection of fluoroquinolone-resistant and heteroresistant Mycobacterium tuberculosis by use of sloppy molecular beacons and dual melting-temperature codes in a real-time PCR assay. J Clin Microbiol. 2011;49:932–40.PubMedPubMedCentralGoogle Scholar
  56. 56.
    de Oliveira M, da Silva-Rocha A, Cardoso-Oelemann M, Gomes H, Fonseca L, Werneck-Barreto A, et al. Rapid detection of resistance against rifampicin in isolates of Mycobacterium tuberculosis from Brazilian patients using a reverse-phase hybridization assay. J Microbiol Methods. 2003;53:335–42.PubMedGoogle Scholar
  57. 57.
    Vogelstein B, Kinsler K. Digital PCR. Proc Natl Acad Sci U S A. 1999;96:9236–41.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Yajko D, Wagner C, Tevere V, Kocagöz T, Hadley W, Chambers H. Quantitative culture of Mycobacterium tuberculosis from clinical sputum specimens and dilution endpoint of its detection by the Amplicor PCR assay. J Clin Microbiol. 1995;33:1944–7.PubMedPubMedCentralGoogle Scholar
  59. 59.
    Diacon A, Patientia R, Venter A, van Helden P, Smith P, McIlleron H, et al. Early bactericidal activity of high-dose rifampin in patients with pulmonary tuberculosis evidenced by positive sputum smears. Antimicrob Agents Chemother. 2007;51:2994–6.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Brindle R, Odhiambo J, Mitchison D. Serial counts of Mycobacterium tuberculosis in sputum as surrogate markers of the sterilising activity of rifampicin and pyrazinamide in treating pulmonary tuberculosis. BMC Pulm Med. 2001;1:2.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Bouakaze C, Keyser C, Gonzalez A, Sougakoff W, Veziris N, Dabernat H, et al. Matrix-assisted laser desorption ionization-time of flight mass spectrometry-based single nucleotide polymorphism genotyping assay using iPLEX gold technology for identification of Mycobacterium tuberculosis complex species and lineages. J Clin Microbiol. 2011;49(9):3292.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Liu Q, Sommer S. Pyrophosphorolysis-activated polymerization (PAP): application to allele-specific amplification. BioTechniques. 2000;29:1072–83.PubMedGoogle Scholar
  63. 63.
    Liu Q, Nguyen VQ, Li X, Sommer SS. Multiplex dosage pyrophosphorolysis-activated polymerization: application to the detection of heterozygous deletions. BioTechniques. 2006;40(5):661–8.PubMedGoogle Scholar
  64. 64.
    Liu Q, Sommer SS. Pyrophosphorolysis-activatable oligonucleotides may facilitate detection of rare alleles, mutation scanning and analysis of chromatin structures. Nucleic Acids Res. 2002;30(2):598–604.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Liu Q, Sommer SS. PAP: detection of ultra rare mutations depends on P* oligonucleotides: “sleeping beauties” awakened by the kiss of pyrophosphorolysis. Hum Mutat. 2004a;23(5):426–36.PubMedGoogle Scholar
  66. 66.
    Liu Q, Sommer SS. Detection of extremely rare alleles by bidirectional pyrophosphorolysis-activated polymerization allele-specific amplification (Bi-PAP-A): measurement of mutation load in mammalian tissues. BioTechniques. 2004b;36(1):156–66.PubMedGoogle Scholar
  67. 67.
    Liu Q, Sommer SS. Pyrophosphorolysis by Type II DNA polymerases: implications for pyrophosphorolysis-activated polymerization. Anal Biochem. 2004c;324(1):22–8.PubMedGoogle Scholar
  68. 68.
    Vargas D, Kramer F, Tyagi S, Marras S. Multiplex real-time PCR assays that measure the abundance of extremely rare mutations associated with cancer. PLoS One. 2016;11:e0156546.PubMedPubMedCentralGoogle Scholar
  69. 69.
    Gootenberg J, Abudayyeh O, Lee J, Essletzbichler P, Dy A, Joung J, et al. Nucleic acid detection with CRISPR-Cas13a/C2c2. Science. 2017;pii: eaam9321.Google Scholar
  70. 70.
    Rock J, Hopkins F, Chavez A, Diallo M, Chase M, Gerrick E, et al. Programmable transcriptional repression in mycobacteria using an orthogonal CRISPR interference platform. Nat Microbiol. 2017;2:16274.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Rice J, Reis A, Rice L, Carver-Brown R, Wangh L. Fluorescent signatures for variable DNA sequences. Nucleic Acids Res. 2012;40:e164.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Huang Q, Liu Z, Liao Y, Chen X, Zhang Y, Li Q. Multiplex fluorescence melting curve analysis for mutation detection with dual-labeled, self-quenched probes. PLoS One. 2011;6:e19206.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Seligman S. Methicillin-resistant staphylococci: genetics of the minority population. J Gen Microbiol. 1966;42:315–22.PubMedGoogle Scholar
  74. 74.
    Ryffel C, Strässle A, Kayser F, Berger-Bächi B. Mechanisms of heteroresistance in methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 1994;38:724–8.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Lim D, Strynadka N. Structural basis for the beta lactam resistance of PBP2a from methicillin-resistant Staphylococcus aureus. Nat Struct Biol. 2002;9:870–6.PubMedGoogle Scholar
  76. 76.
    Aiba Y, Katayama Y, Hishinuma T, Murakami-Kuroda H, Cui L, Hiramatsu K. Mutation of RNA polymerase β-subunit gene promotes heterogeneous-to-homogeneous conversion of β-lactam resistance in methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2013;57:4861–71.PubMedPubMedCentralGoogle Scholar
  77. 77.
    Alam M, Petit R, Crispell E, Thornton T, Conneely K, Jiang Y, et al. Dissecting vancomycin-intermediate resistance in Staphylococcus aureus using genome-wide association. Genome Biol Evol. 2014;6:1174–85.PubMedPubMedCentralGoogle Scholar
  78. 78.
    Saravolatz SN, Martin H, Pawlak J, Johnson LB, Saravolatz LD. Ceftaroline-heteroresistant Staphylococcus aureus. Antimicrob Agents Chemother. 2014;58(6):3133.PubMedPubMedCentralGoogle Scholar
  79. 79.
    Cui L, Neoh H, Shoji M, Hiramatsu K. Contribution of vraSR and graSR point mutations to vancomycin resistance in vancomycin-intermediate Staphylococcus aureus. Antimicrob Agents Chemother. 2009;53:1231–4.PubMedPubMedCentralGoogle Scholar
  80. 80.
    Boyle-Vavra S, Berke S, Lee J, Daum R. Reversion of the glycopeptide resistance phenotype in Staphylococcus aureus clinical isolates. Antimicrob Agents Chemother. 2000;44:272–7.PubMedPubMedCentralGoogle Scholar
  81. 81.
    Cameron D, Ward D, Kostoulias X, Howden B, Moellering R, Eliopoulos G, et al. Serine/threonine phosphatase Stp1 contributes to reduced susceptibility to vancomycin and virulence in Staphylococcus aureus. J Inf Dis. 2012;205:1677–87.Google Scholar
  82. 82.
    Gao W, Cameron D, Davies J, Kostoulias X, Stepnell J, Tuck K, et al. The RpoB H481Y rifampicin resistance mutation and an active stringent response reduce virulence and increase resistance to innate immune responses in Staphylococcus aureus. J Inf Dis. 2013;207:929–39.Google Scholar
  83. 83.
    Majcherczyk P, Barblan J, Moreillon P, Entenza J. Development of glycopeptide-intermediate resistance by Staphylococcus aureus leads to attenuated infectivity in a rat model of endocarditis. Microb Pathog. 2008;45:408–14.PubMedGoogle Scholar
  84. 84.
    Peleg A, Monga D, Pillai S, Mylonakis E, Moellering R, Eliopoulos G. Reduced susceptibility to vancomycin influences pathogenicity in Staphylococcus aureus infection. J Inf Dis. 2009;199:532–6.Google Scholar
  85. 85.
    Donnio P, Oliveira D, Faria N, Wilhelm N, LeCoustumier A, deLencastre H. Partial excision of the chromosomal cassette containing the methicillin resistance determinant results in methicillin-susceptible Staphylococcus aureus. J Clin Microbiol. 2005;43:4191–3.PubMedPubMedCentralGoogle Scholar
  86. 86.
    Tenover F, Moellering R. The rationale for revising the Clinical and Laboratory Standards Institute vancomycin minimal inhibitory concentration interpretive criteria for Staphylococcus aureus. Clin Inf Dis. 2007;44:1208–15.Google Scholar
  87. 87.
    Satola S, Farley M, Anderson K, Patel J. Comparison of detection methods for heteroresistant vancomycin-intermediate Staphylococcus aureus, with the population analysis profile method as the reference method. J Clin Microbiol. 2011;49:177–83.PubMedGoogle Scholar
  88. 88.
    Chen C, Huang Y, Chiu C. Multiple pathways of cross-resistance to glycopeptides and daptomycin in persistent MRSA bacteraemia. J Antimicrob Chemother. 2015;70:2965–72.PubMedGoogle Scholar
  89. 89.
    Hafer C, Lin Y, Kornblum J, Lowy F, Uhlemann A. Contribution of selected gene mutations to resistance in clinical isolates of vancomycin-intermediate Staphylococcus aureus. Antimicrob Agents Chemother. 2012;56:5845–51.PubMedPubMedCentralGoogle Scholar
  90. 90.
    Khatib R, Jose J, Musta A, Sharma M, Fakih M, Johnson L, et al. Relevance of vancomycin-intermediate susceptibility and heteroresistance in methicillin-resistant Staphylococcus aureus bacteraemia. J Antimicrob Chemother. 2011;66:1594–9.PubMedGoogle Scholar
  91. 91.
    Huang S, Chen Y, Chuang Y, Chiu S, Fung C, Lu P, et al. Prevalence of vancomycin-intermediate Staphylococcus aureus (VISA) and heterogeneous VISA among methicillin-resistant S. aureus with high vancomycin minimal inhibitory concentrations in Taiwan: a multicenter surveillance study, 2012–2013. J Microbiol Immunol Infect. 2016;49:701–7.PubMedGoogle Scholar
  92. 92.
    Chung D, Lee C, Kang Y, Baek J, Kim S, Ha Y, et al. Genotype-specific prevalence of heterogeneous vancomycin-intermediate Staphylococcus aureus in Asian countries. Int J Antimicrob Agents. 2015;46:338–41.PubMedGoogle Scholar
  93. 93.
    Sancak B, Yagci S, Gür D, Gülay Z, Ogunc D, Söyletir G, et al. Vancomycin and daptomycin minimum inhibitory concentration distribution and occurrence of heteroresistance among methicillin-resistant Staphylococcus aureus blood isolates in Turkey. BMC Infect Dis. 2013;13:583.PubMedPubMedCentralGoogle Scholar
  94. 94.
    Gomes D, Ward K, LaPlante K. Clinical implications of vancomycin heteroresistant and intermediately susceptible Staphylococcus aureus. Pharmacotherapy. 2015;35:424–32.PubMedGoogle Scholar
  95. 95.
    Claeys K, Lagnf A, Hallesy J, Compton MT, Gravelin A, Davis S, et al. Pneumonia caused by methicillin-resistant Staphylococcus aureus: does vancomycin heteroresistance matter? Antimicrob Agents Chemother. 2016;60:1708–16.PubMedPubMedCentralGoogle Scholar
  96. 96.
    Zhao X, Drlica K. Restricting the selection of antibiotic-resistant mutants: a general strategy derived from fluoroquinolone studies. Clin Inf Dis. 2001;33(Suppl 3):S147–S56.Google Scholar
  97. 97.
    Rybak M, Lomaestro B, Rotschafer J, Moellering R, Craig W, Billeter M, et al. Therapeutic monitoring of vancomycin in adults summary of consensus recommendations from the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Pharmacotherapy. 2009;29:1275–9.PubMedGoogle Scholar
  98. 98.
    Mei Q, Ye Y, Zhu Y, Cheng J, Yang HF, Liu Y, et al. Use of Monte Carlo simulation to evaluate the development of vancomycin resistance in meticillin-resistant Staphylococcus aureus. Int J Antimicrob Agents. 2015a;45(6):652.PubMedGoogle Scholar
  99. 99.
    Khatib R, Sharma M, Johnson L, Riederer K, Shemes S, Szpunar S. Decreasing prevalence of isolates with vancomycin heteroresistance and vancomycin minimum inhibitory concentrations ≥2 mg/L in methicillin-resistant Staphylococcus aureus over 11 years: potential impact of vancomycin treatment guidelines. Diagn Microbiol Infect Dis. 2015;82:245–8.PubMedGoogle Scholar
  100. 100.
    Ikonomidis A, Neou E, Gogou V, Vrioni G, Tsakris A, Pournaras S. Heteroresistance to meropenem in carbapenem-susceptible Acinetobacter baumannii. J Clin Microbiol. 2009;47:4055–9.PubMedPubMedCentralGoogle Scholar
  101. 101.
    Hung K, Wang M, Huang A, Yan J, Wu J. Heteroresistance to cephalosporins and penicillins in Acinetobacter baumannii. J Clin Microbiol. 2012;50:721–6.PubMedPubMedCentralGoogle Scholar
  102. 102.
    Choi H, Kil M, Choi J, Kim S, Park K, Kim Y, et al. Characterisation of successive Acinetobacter baumannii isolates from a deceased haemophagocytic lymphohistiocytosis patient. Int J Antimicrob Agents. 2017;49:102–6.PubMedGoogle Scholar
  103. 103.
    Rodríguez C, Nastro M, Fiorilli G, Dabos L, Lopez-Calvo J, Fariña M, et al. Trends in the resistance profiles of Acinetobacter baumannii endemic clones in a university hospital of Argentina. J Chemother. 2016;28:25–7.PubMedGoogle Scholar
  104. 104.
    Álvarez-Pérez S, Blanco J, Harmanus C, Kuijper E, García M. Subtyping and antimicrobial susceptibility of Clostridium difficile PCR ribotype 078/126 isolates of human and animal origin. Vet Microbiol. 2017;199:15–22.PubMedGoogle Scholar
  105. 105.
    Tran T, Jaijakul S, Lewis C, Diaz L, Panesso D, Kaplan H, et al. Native valve endocarditis caused by Corynebacterium striatum with heterogeneous high-level daptomycin resistance: collateral damage from daptomycin therapy? Antimicrob Agents Chemother. 2012;56:3461–4.PubMedPubMedCentralGoogle Scholar
  106. 106.
    Ma W, Sun J, Yang S, Zhang L. Epidemiological and clinical features for cefepime heteroresistant Escherichia coli infections in Southwest China. Eur J Clin Microbiol Infect Dis. 2016;35:571–8.PubMedGoogle Scholar
  107. 107.
    Sun J, Huang S, Yang S, Pu S, Zhang C, Zhang LZ. Impact of carbapenem heteroresistance among clinical isolates of invasive Escherichia coli in Chongqing, southwestern China. Clin Microbiol Infect. 2014;21:469.e1–10.Google Scholar
  108. 108.
    Cherkaoui A, Diene S, Renzoni A, Emonet S, Renzi G, François P, et al. Imipenem heteroresistance in nontypeable Haemophilus influenzae is linked to a combination of altered PBP3, slow drug influx and direct efflux regulation. Clin Microbiol Infect. 2017;23:118.e9–e19.Google Scholar
  109. 109.
    Ben-Mansour K, Fendri C, Battikh H, Garnier M, Zribi M, Jlizi A, et al. Multiple and mixed Helicobacter pylori infections: comparison of two epidemiological situations in Tunisia and France. Infect Genet Evol. 2016;37:43–8.PubMedGoogle Scholar
  110. 110.
    Tato M, Morosini M, García L, Albertí S, Coque M, Cantón R. Carbapenem heteroresistance in VIM-1-producing Klebsiella pneumoniae isolates belonging to the same clone: consequences for routine susceptibility testing. J Clin Microbiol. 2010;48:4089–93.PubMedPubMedCentralGoogle Scholar
  111. 111.
    Pournaras S, Kristo I, Vrioni G, Ikonomidis A, Poulou A, Petropoulou D, et al. Characteristics of meropenem heteroresistance in Klebsiella pneumoniae carbapenemase (KPC)-producing clinical isolates of K. pneumoniae. J Clin Microbiol. 2010;48:2601–4.PubMedPubMedCentralGoogle Scholar
  112. 112.
    Meletis G, Tzampaz E, Sianou E, Tzavaras I, Sofianou D. Colistin heteroresistance in carbapenemase-producing Klebsiella pneumoniae. J Antimicrob Chemother. 2011;66:946–7.PubMedGoogle Scholar
  113. 113.
    Zhang X, Zhao B, Liu L, Zhu Y, Zhao Y, Jin Q. Subpopulation analysis of heteroresistance to fluoroquinolone in Mycobacterium tuberculosis isolates from Beijing, China. J Clin Microbiol. 2012;50:1471–3.PubMedPubMedCentralGoogle Scholar
  114. 114.
    Pournaras S, Ikonomidis A, Markogiannakis A, Spanakis N, Maniatis A, Tsakris A. Characterization of clinical isolates of Pseudomonas aeruginosa heterogeneously resistant to carbapenems. J Med Microbiol. 2007;56:66–70.PubMedGoogle Scholar
  115. 115.
    Mei S, Gao Y, Zhu C, Dong C, Chen Y. Research of the heteroresistance of Pseudomonas aeruginosa to imipenem. Int J Clin Exp Med. 2015b;8:6129–32.PubMedPubMedCentralGoogle Scholar
  116. 116.
    Hjort K, Nicoloff H, Andersson D. Unstable tandem gene amplification generates heteroresistance (variation in resistance within a population) to colistin in Salmonella enterica. Mol Microbiol. 2016;102:274–89.PubMedGoogle Scholar
  117. 117.
    Morand B, Mühlemann K. Heteroresistance to penicillin in Streptococcus pneumoniae. Proc Natl Acad Sci U S A. 2007;104:14098–103.PubMedPubMedCentralGoogle Scholar
  118. 118.
    Selgrad M, Tammer I, Langner C, Bornschein J, Meißle J, Kandulski A, et al. Different antibiotic susceptibility between antrum and corpus of the stomach, a possible reason for treatment failure of Helicobacter pylori infection. World J Gastroenterol. 2014;20:16245–51.PubMedPubMedCentralGoogle Scholar
  119. 119.
    Jayol A, Nordmann P, Brink A, Poirel L. Heteroresistance to colistin in Klebsiella pneumoniae associated with alterations in the PhoPQ regulatory system. Antimicrob Agents Chemother. 2015;59:2780–4.PubMedPubMedCentralGoogle Scholar
  120. 120.
    Kling A, Lukat P, Almeida DV, Bauer A, Fontaine E, Sordello S, et al. Antibiotics. Targeting DnaN for tuberculosis therapy using novel griselimycins. Science. 2015;348:1106–12.PubMedGoogle Scholar
  121. 121.
    Band V, Crispell B, Napier B, Herrera C, Tharp G, Vavikolanu K, et al. Antibiotic failure mediated by a resistant subpopulation in Enterobacter cloacae. Nat Microbiol. 2016;1:16053.PubMedPubMedCentralGoogle Scholar
  122. 122.
    Engel H, Gutiérrez-Fernández J, Flückiger C, Martínez-Ripoll M, Mühlemann K, Hermoso J, et al. Heteroresistance to fosfomycin is predominant in Streptococcus pneumoniae and depends on the murA1 gene. Antimicrob Agents Chemother. 2013;57:2801–108.PubMedPubMedCentralGoogle Scholar
  123. 123.
    Sedláková M, Urbánek K, Vojtová V, Suchánková H, Imwensi P, Kolář M. Antibiotic consumption and its influence on the resistance in Enterobacteriaceae. BMC Res Notes. 2014;7:454.PubMedPubMedCentralGoogle Scholar
  124. 124.
    Antoniadou A, Kanellakopoulou K, Kanellopoulou M, Polemis M, Koratzanis G, Papademetriou E, et al. Impact of a hospital-wide antibiotic restriction policy program on the resistance rates of nosocomial Gram-negative bacteria. Scand J Infect Dis. 2013;45:438–45.PubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Public Health Research InstituteNew Jersey Medical School, Rutgers Biomedical and Health SciencesNewarkUSA
  2. 2.Departments of Medicine and MicrobiologyNew York University School of MedicineNew YorkUSA
  3. 3.Department of Microbiology, Biochemistry, & Molecular GeneticsNew Jersey Medical School, Rutgers Biomedical and Health SciencesNewarkUSA
  4. 4.State Key Laboratory of Molecular Vaccinology and Molecular DiagnosticsSchool of Public Health, Xiamen UniversityXiamenChina

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