Skip to main content Accessibility help

Defining Relatedness in Studies of Transmission of Antimicrobial-Resistant Organisms Variability in Definitions across Studies and Impact of Different Approaches on Study Conclusions

  • Rachel M. Greenblatt (a1), Jennifer H. Han (a2), Irving Nachamkin (a3), Pam Tolomeo (a4) (a5) and Ebbing Lautenbach (a2) (a4) (a5)...



Comparison of studies evaluating patient-to-patient transmission of organisms is difficult, given the lack of standardized criteria. We used fluoroquinolone-resistant Escherichia coli (FQREC) as a model to characterize variability in definitions of relatedness across studies and to evaluate the resultant impact on study conclusions.


Narrative review and cohort study.


The narrative review compared relatedness criteria across studies of FQREC. Additionally, an existing database was used to compare relatedness of isolates on the basis of molecular criteria alone versus molecular plus clinical criteria with different temporal cutoffs (hospitalization overlap of ≥1 day or allowance for nonoverlap of hospitalization dates of ≤7 days or ≤30 days).


Forty-six articles met narrative review inclusion criteria. Sixteen studies exclusively utilized molecular criteria to define relatedness. Thirty studies included molecular and clinical criteria. Of these, 6 included temporal data (ie, time period of isolate identification), 10 included patient location, and 14 included proximity and temporal criteria. For the database analysis, 353 patients were colonized with FQREC. There were 2 main clusters containing 48 and 17 related isolates within 49 pulsed-field gel electrophoresis types. Among the clusters, 18.4% of isolates were related by molecular criteria. Incorporating clinical criteria, fewer isolates were considered related: 5.7% of isolates using 30-day criteria, 3.1% using 7-day criteria, and 1.4% using 1-day overlap.


There is considerable variability in definitions of relatedness of FQREC. Utilizing molecular criteria alone to define relatedness overestimates transmission compared with definitions including clinical criteria. Standard definitions of relatedness in studies of antimicrobial-resistant organisms are needed.


Corresponding author

Division of Infectious Diseases, Department of Medicine, Hospital of the University of Pennsylvania, 3400 Spruce Street, Third Floor, Silverstein Building, Suite E, Philadelphia, PA 19104 (


Hide All
1. Society for Healthcare Epidemiology of America; Infectious Diseases Society of America; Pediatric Infectious Diseases Society. Policy statement on antimicrobial stewardship by the Society for Healthcare Epidemiology of America (SHEA), the Infectious Diseases Society of America (IDSA), and the Pediatric Infectious Diseases Society (PIDS). Infect Control Hosp Epidemiol 2012;33: 322327.
2. Harris, AD, Kotetishvili, M, Shurland, S, et al. How important is patient-to-patient transmission in extended-spectrum β-lactamase Escherichia coli acquisition. Am J Infect Control 2007;35: 97101.
3. Harris, AD, Perencevich, EN, Johnson, JK, et al. Patient-to-patient transmission is important in extended-spectrum β-lactamase-producing Klebsiella pneumoniae acquisition. Clin Infect Dis 2007;45:13471350.
4. Bauernfeind, A, Abele-Horn, M, Emmerling, P, Jungwirth, R. Multiclonal emergence of ciprofloxacin-resistant clinical isolates of Escherichia coli and Klebsiella pneumoniae . J Antimicrob Chemother 1994;34:10741076.
5. Pitout, JD, Wei, Y, Church, DL, Gregson, DB. Surveillance for plasmid-mediated quinolone resistance determinants in Enter-obacteriaceae within the Calgary Health Region, Canada: the emergence of aac(6′)-Ib-cr. J Antimicrob Chemother 2008;61: 9991002.
6. van Hees, BC, Tersmette, M, Willems, RJ, de Jong, B, Biesma, D, van Hannen, EJ. Molecular analysis of ciprofloxacin resistance and clonal relatedness of clinical Escherichia coli isolates from haematology patients receiving ciprofloxacin prophylaxis. J Antimicrob Chemother 2011;66:17391744.
7. Christiansen, N, Nielsen, L, Jakobsen, L, Stegger, M, Hansen, LH, Frimodt-Moller, N. Fluoroquinolone resistance mechanisms in urinary tract pathogenic Escherichia coli isolated during rapidly increasing fluoroquinolone consumption in a low-use country. Microb Drug Resist 2011;17:395406.
8. Kariuki, S, Revathi, G, Corkill, J, et al. Escherichia coli from community-acquired urinary tract infections resistant to fluoroquinolones and extended-spectrum beta-lactams. J Infect Dev Ctries 2007;1:257262.
9. Lautenbach, E, Metlay, JP, Mao, X, et al. The prevalence of fluoroquinolone resistance mechanisms in colonizing Escherichia coli isolates recovered from hospitalized patients. Clin Infect Dis 2010;51:280285.
10. Lautenbach, E, Harris, AD, Perencevich, EN, Nachamkin, I, Tolomeo, P, Metlay, JP. Test characteristics of perirectal and rectal swab compared to stool sample for detection of fluoroquino-lone-resistant Escherichia coli in the gastrointestinal tract. Antimicrob Agents Chemother 2005;49:798800.
11. Johnson, JK, Smith, G, Lee, MS, et al. The role of patient-to-patient transmission in the acquisition of imipenem-resistant Pseudomonas aeruginosa colonization in the intensive care unit. J Infect Dis 2009;200:900905.
12. Baum, HV, Franz, U, Geiss, HK. Prevalence of ciprofloxacin-resistant Escherichia coli in hematologic-oncologic patients. Infection 2000;28:278281.
13. Blanco, J, Mora, A, Mamani, R, et al. National survey of Escherichia coli causing extraintestinal infections reveals the spread of drug-resistant clonal groups 025b:H4-B2-ST131, 015:H1-D-ST393 and CGA-D-ST69 with high virulence gene content in Spain. J Antimicrob Chemother 2011;66:20112021.
14. Carratala, J, Fernandez-Sevilla, A, Tubau, F, Dominguez, MA, Gudiol, F. Emergence of fluoroquinolone-resistant Escherichia coli in fecal flora of cancer patients receiving norfloxacin prophylaxis. Antimicrob Agents Chemother 1996;40:503505.
15. Chang, TM, Lu, PL, Li, HH, Chang, CY, Chen, TC, Chang, LL. Characterization of fluoroquinolone resistance mechanisms and their correlation with the degree of resistance to clinically used fluoroquinolones among Escherichia coli isolates. J Chemother 2007;19:488494.
16. Chen, JY, Siu, LK, Chen, YH, Lu, PL, Ho, M, Peng, CF. Molecular epidemiology and mutations at gyrA and parC genes of ciprofloxacin-resistant Escherichia coli isolates from a Taiwan medical center. Microb Drug Resist 2001;7:4753.
17. Cheong, HJ, Yoo, CW, Sohn, JW, Kim, WJ, Kim, MJ, Park, SC. Bacteremia due to quinolone-resistant Escherichia coli in a teaching hospital in South Korea. Clin Infect Dis 2001;33:4853.
18. Eom, JS, Hwang, BY, Sohn, JW, et al. Clinical and molecular epidemiology of quinolone-resistant Escherichia coli isolated from urinary tract infection. Microb Drug Resist 2002;8:227234.
19. Tenover, FC, Arbeit, RD, Goering, RV, et al. Interpreting chromosomal DNA restriction patterns produced by pulsed-field gel electrophoresis: criteria for bacterial strain typing. J Clin Microbiol 1995;33:22332239.
20. Garau, J, Xercavins, M, Rodriguez-Carballeira, M, et al. Emergence and dissemination of quinolone-resistant Escherichia coli in the community. Antimicrob Agents Chemother 1999;43: 27362741.
21. Grude, N, Strand, L, Mykland, H, et al. Fluoroquinolone-resistant uropathogenic Escherichia coli in Norway: evidence of clonal spread. Clin Microbiol Infect 2008;14:498500.
22. Johnson, JR, Johnston, B, Clabots, C, et al. Escherichia coli sequence type ST131 as an emerging fluoroquinolone-resistant uropathogen among renal transplant recipients. Antimicrob Agents Chemother 2010;54:546550.
23. Johnson, JR, Johnston, B, Clabots, C, Kuskowski, MA, Castanheira, M. Escherichia coli sequence type ST131 as the major cause of serious multidrug-resistant E. coli infections in the United States. Clin Infect Dis 2010;51:286294.
24. Kern, WV, Andriof, E, Oethinger, M, Kern, P, Hacker, J, Marre, R. Emergence of fluoroquinolone-resistant Escherichia coli at a cancer center. Antimicrob Agents Chemother 1994;38:681687.
25. Kern, WV, Klose, K, AS, Jellen-Ritter, et al. Fluoroquinolone resistance of Escherichia coli at a cancer center: epidemiologic evolution and effects of discontinuing prophylactic fluoroquinolone use in neutropenic patients with leukemia. Eur J Clin Microbiol Infect Dis 2005;24:111118.
26. Kuntaman, K, Lestari, ES, JA, Severin, et al. Fluoroquinolone-resistant Escherichia coli, Indonesia. Emerg Infect Dis 2005;11:13631369.
27. Lautenbach, E, NO, Fishman, JP, Metlay, et al. Phenotypic and genotypic characterization of fecal Escherichia coli isolates with decreased susceptibility to fluoroquinolones: results from a large hospital-based surveillance initiative. J Infect Dis 2006; 194: 7985.
28. Lehn, N, Stower-Hoffmann, J, Kott, T, et al. Characterization of clinical isolates of Escherichia coli showing high levels of fluoroquinolone resistance. J Clin Microbiol 1996;34:597602.
29. JN, Maslow, Lee, B, Lautenbach, E. Fluoroquinolone-resistant Escherichia coli carriage in long-term care facility. Emerg Infect Dis 2005;11:889894.
30. LC, McDonald, FJ, Chen, HJ, Lo, et al. Emergence of reduced susceptibility and resistance to fluoroquinolones in Escherichia coli in Taiwan and contributions of distinct selective pressures. Antimicrob Agents Chemother 2001;45:30843091.
31. CN, Mihu, PR, Rhomberg, RN, Jones, Coyle, E, RA, Prince, KV, Rolston. Escherichia coli resistance to quinolones at a comprehensive cancer center. Diagn Microbiol Infect Dis 2010;67:266269.
32. Oethinger, M, Conrad, S, Kaifel, K, et al. Molecular epidemiology of fluoroquinolone-resistant Escherichia coli bloodstream isolates from patients admitted to European cancer centers. Antimicrob Agents Chemother 1996;40:387392.
33. Oethinger, M, AS, Jellen-Ritter, Conrad, S, Marre, R, WV, Kern. Colonization and infection with fluoroquinolone-resistant Escherichia coli among cancer patients: clonal analysis. Infection 1998; 26:379384.
34. YH, Park, JH, Yoo, DH, Huh, YK, Cho, JH, Choi, WS, Shin. Molecular analysis of fluoroquinolone-resistance in Escherichia coli on the aspect of gyrase and multiple antibiotic resistance (mar) genes. Yonsei Med J 1998;39:534540.
35. AS, Pereira, SS, Andrade, Monteiro, J, HS, Sader, AC, Pignatari, AC, Gales. Evaluation of the susceptibility profiles, genetic similarity and presence of qnr gene in Escherichia coli resistant to ciprofloxacin isolated in Brazilian hospitals. Braz J Infect Dis 2007;11:4043.
36. MA, Pfaller, RJ, Hollis, HJ, Sader. Chromosomal restriction fragment analysis by pulsed-field gel electrophoresis. In: HD, Isenberg. Clinical Microbiology Procedures Handbook. 2, suppl. 1. New York: American Society for Microbiology, 1992:10.5c.1-10.5.c.12.
37. Perrin, M, PY, Donnio, Heurtin-Lecorre, C, MF, Travert, JL, Avril. Comparative antimicrobial resistance and genomic diversity of Escherichia coli isolated from urinary tract infections in the community and in hospitals. J Hosp Infect 1999;41:273279.
38. Reuter, S, WV, Kern, Sigge, A, et al. Impact of fluoroquinolone prophylaxis on reduced infection-related mortality among patients with neutropenia and hematologic malignancies. Clin Infect Dis 2005;40:10871093.
39. PR, Rhomberg, TR, Fritsche, HS, Sader, RN, Jones. Clonal occurrences of multidrug-resistant gram-negative bacilli: report from the Meropenem Yearly Susceptibility Test Information Collection Surveillance Program in the United States (2004). Diagn Microbiol Infect Dis 2006;54:249257.
40. WH, Sheng, YC, Chen, JT, Wang, SC, Chang, KT, Luh, WC, Hsieh. Emerging fluoroquinolone-resistance for common clinically important gram-negative bacteria in Taiwan. Diagn Microbiol Infect Dis 2002;43:141147.
41. JH, Shin, HJ, Jung, JY, Lee, HR, Kim, JN, Lee, CL, Chang. High rates of plasmid-mediated quinolone resistance QnrB variants among ciprofloxacin-resistant Escherichia coli and Klebsiella pneumoniae from urinary tract infections in Korea. Microb Drug Resist 2008;14:221226.
42. Tascini, C, Menichetti, F, Bozza, S, et al. Molecular typing of fluoroquinolone-resistant and fluoroquinolone-susceptible Escherichia coli isolated from blood of neutropenic cancer patients in a single center. Clin Microbiol Infect 1999;5:457461.
43. Uchida, Y, Mochimaru, T, Morokuma, Y, et al. Clonal spread in Eastern Asia of ciprofloxacin-resistant Escherichia coli serogroup 025 strains, and associated virulence factors. Int J Antimicrob Agents 2010;35:444450.
44. Uchida, Y, Mochimaru, T, Morokuma, Y, et al. Geographic distribution of fluoroquinolone-resistant Escherichia coli strains in Asia. Int J Antimicrob Agents 2010;35:387391.
45. CR, Usein, Tatu-Chitoiu, D, Nica, M, et al. Characteristics of Romanian fluoroquinolone-resistant human clinical Escherichia coli isolates. Roum Arch Microbiol Immunol 2008;67:2329.
46. van Belkum, A, Goessens, W, van der Schee, C, et al. Rapid emergence of ciprofloxacin-resistant enterobacteriaceae containing multiple gentamicin resistance-associated integrons in a Dutch hospital. Emerg Infect Dis 2001;7:862871.
47. MG, van Kraaij, AW, Dekker, Peters, E, Fluit, A, LF, Verdonck, Rozenberg-Arska, M. Emergence and infectious complications of ciprofloxacin-resistant Escherichia coli in haematological cancer patients. Eur J Clin Microbiol Infect Dis 1998;17:591592.
48. KJ, Vigil, JA, Adachi, Aboufaycal, H, et al. Multidrug-resistant Escherichia coli bacteremia in cancer patients. Am J Infect Control 2009;37:741745.
49. KJ, Vigil, JR, Johnson, BD, Johnston, et al. Escherichia coli pyom-yositis: an emerging infectious disease among patients with hematologic malignancies. Clin Infect Dis 2010;50:374380.
50. Wagenlehner, F, Stower-Hoffmann, J, Schneider-Brachert, W, KG, Naber, Lehn, N. Influence of a prophylactic single dose of ciprofloxacin on the level of resistance of Escherichia coli to fluoroquinolones in urology. Int J Antimicrob Agents 2000; 15: 207211.
51. Wang, A, Yang, Y, Lu, Q, et al. Presence of qnr gene in Escherichia coli and Klebsiella pneumoniae resistant to ciprofloxacin isolated from pediatric patients in China. BMC Infect Dis 2008;8:68.
52. LN, Xia, Li, L, CM, Wu, et al. A survey of plasmid-mediated fluoroquinolone resistance genes from Escherichia coli isolates and their dissemination in Shandong, China. Foodborne Pathog Dis 2010;7:207215.
53. JH, Yoo, DH, Huh, JH, Choi, et al. Molecular epidemiological analysis of quinolone-resistant Escherichia coli causing bacteremia in neutropenic patients with leukemia in Korea. Clin Infect Dis 1997;25:13851391.


Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed