Skip to main content Accessibility help

Increased Susceptibility to Vancomycin-Resistant Enterococcus Intestinal Colonization Persists After Completion of Anti-Anaerobic Antibiotic Treatment in Mice

  • Usha Stiefel (a1), Nicole J. Pultz (a2), Marion S. Helfand (a2) (a3) and Curtis J. Donskey (a2) (a3)



Antibiotic-associated disruption of the indigenous intestinal microflora may persist beyond the treatment period. Although piperacillin/tazobactam inhibits the establishment of vancomycin-resistant Enterococcus (VRE) stool colonization in mice during treatment, we hypothesized that this agent and other anti-anaerobic antibiotics would increase susceptibility to colonization during the period of recovery of the intestinal microflora.


Mice received 104 colony-forming units of vancomycin-resistant E. faecium by orogastric inoculation 2, 5, or 10 days after completing 5 days of subcutaneous antibiotic treatment, or both during and 2 days after the completion of treatment. Denaturing gradient gel electrophoresis (DGGE) was performed to assess changes in the intestinal microflora.


Anti-anaerobic antibiotics (ie, piperacillin/tazobactam, cefoxitin, and clindamycin) caused significant disruption of the indigenous microflora (mean DGGE similarity indices ≤ 27% in comparison with saline controls) and promoted the establishment of high-density colonization when VRE was inoculated 2 or 5, but not 10, days following treatment (P < .001). Piperacillin/tazobactam exhibited a biphasic effect on the establishment of colonization (ie, inhibition when exposed to VRE during treatment and promotion when exposed to VRE after discontinuation of treatment), resulting in greater overall promotion of colonization than did agents with minimal anti-anaerobic activity (ie, levofloxacin, cefepime, and aztreonam) when VRE was inoculated both during and 2 days after treatment (P< .001).


Patients receiving anti-anaerobic antibiotics, including piperacillin/tazobactam, may be susceptible to the establishment of high-density VRE colonization during the period of recovery of the anaerobic microflora.


Corresponding author

Infectious Diseases Section (111 W), Louis Stokes Cleveland VA Medical Center, 10701 East Blvd., Cleveland, OH 44106


Hide All
1.Donskey, CJ, Hanrahan, JA, Hutton, RA, Rice, LB. Effect of parenteral antibiotic administration on persistence of vancomycin-resistant Enterococcus faecium in the mouse gastrointestinal tract. J Infect Dis 1999;180:384390.
2.Donskey, CJ, Hanrahan, JA, Hutton, RA, Rice, LB. Effect of parenteral antibiotic administration on the establishment of colonization with vancomycin-resistant Enterococcus faecium in the mouse gastrointestinal tract. J Infect Dis 2000;181:18301833.
3.Donskey, CJ, Chowdhry, TK, Hecker, MT, et al.Effect of antibiotic therapy on the density of vancomycin-resistant enterococci in the stool of colonized patients. N Engl J Med 2000;343:19251932.
4.Donskey, CF, Hoyen, CK, Das, SM, Farmer, S, Dery, M, Bonomo, RA. Effect of oral Bacillus coagulans administration on density and persistence of colonization with vancomycin-resistant enterococci in the mouse gastrointestinal tract. Lett Appl Microbiol 2001;33:8488.
5.Donskey, CJ, Hoyen, CK, Das, SM, Helfand, MS, Hecker, MT. Recurrence of vancomycin-resistant Enterococcus stool colonization during antibiotic therapy. Infect Control Hasp Epidemiol 2002;23:436440.
6.Baden, LR, Critchley, IA, Sahm, DF, et al.Molecular characterization of vancomycin-resistant enterococci repopulating the gastrointestinal tract following treatment with a novel glycolipodepsipeptide, ramo-planin. J Clin Microbiol 2002;40:11601163.
7.Finegold, SM, Mathisen, GE, George, WL. Changes in human intestinal flora related to the administration of antimicrobial agents. In: Hentges, D, ed. Human Intestinal Microflora in Health and Disease. New York: Academic Press; 1983:355446.
8.Vollaard, EJ, Clasener, HAL. Colonization resistance. Antimicrob Agents Chemother 1994;38:409414.
9.Nord, CE, Heimdahl, A, Kager, L, Malmborg, AS. The impact of different antimicrobial agents on the normal gastrointestinal microflora of humans. Rev Infect Dis 1984;6(suppl 1):S270S275.
10.Mulligan, ME, Citron, D, Gabay, E, Kirby, BD, Georgi, WL, Finegold, SM. Alterations in human fecal flora, including ingrowth of Clostridium difficile, related to cefoxitin therapy. Antimicrob Agents Chemother 1984;26:343346.
11.Kager, L, Liljeqvist, L, Malmborg, AS, Nord, CE. Effect of clindamycin prophylaxis on the colonic microflora in patients undergoing colorectal surgery. Antimicrob Agents Chemother 1981;20:736740.
12.Nord, CE, Brismar, B, Hasholm-Tengve, B, Tunevall, G. Effect of piperacillin/tazobactam therapy on intestinal microflora. Scand J Infect Dis 1992;24:209213.
13.Bacher, K, Schaeffer, M, Lode, H, Nord, CE, Borner, K, Koeppe, P. Multiple dose pharmacokinetics, safety, and effects on faecal microflora, of cefepime in healthy volunteers. J Antimicrob Chemother 1992;30:365375.
14.Freireich, EJ, Gehan, EA, Rail, DP, Schmidt, LH, Skipper, HE. Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey and man. Cancer Chemotherapy Reports 1966;50:219244.
15.Donskey, CJ, Hujer, A, Das, SM, Pultz, NJ, Bonomo, RA, Rice, LB. Use of denaturing gradient gel electrophoresis for analysis of the stool microbiota of hospitalized patients. J Microbiol Methods 2003;54:249256.
16.Quale, J, Landman, D, Saurina, G, Atwood, E, DiTore, V, Patel, K. Manipulation of a hospital antimicrobial formulary to control an outbreak of vancomycin-resistant enterococci. Clin Infect Dis 1996;23:10201025.
17.Bradley, SJ, Wilson, ALT, Allen, MC, Sher, HA, Goldstone, AH, Scott, GM. The control of hyperendemic glycopeptide-resistant Enterococcus species on a haematology unit by changing antibiotic usage. J Antimicrob Chemother 1999;43:261266.
18.May, AK, Melton, SM, McGwin, G, Cross, JM, Moser, SA, Rue, LW. Reduction of vancomycin-resistant enterococcal infections by limitation of broad-spectrum cephalosporin use in a trauma and burn intensive care unit. Shock 2000;14:259264.
19.Donskey, CJ, Schreiber, JR, Jacobs, MR, et al.A polyclonal outbreak of predominantly VanB vancomycin-resistant enterococci in Northeast Ohio. Clin Infect Bis 1999;29:573579.
20.Maraki, S, Barbounakis, E, Chatzinikolaou, I, et al.Effects of cefepime, cefixime, and ceftibuten on murine gut colonization by Candida albicans. Chemotherapy 1998;44:405408.
21.Hoyen, CK, Pultz, NJ, Paterson, DL, Aran, DC, Donskey, CJ. Effect of parenteral antibiotic administration on the establishment of intestinal colonization with extended-spectrum β-lactamase-producing Klebsiella pneumoniae in mice. Antimicrob Agents Chemother 2003;47:36103612.
22.Patterson, JE, Hardin, TC, Kelly, CA, Garcia, RC, Jorgenson, JH. Association of antibiotic utilization measures and control of multiple-drug resistance in Klebsiella pneumoniae. Infect Control Hosp Epidemiol 2000;21:455458.
23.Bhalla, A, Pultz, NJ, Ray, AJ, Hoyen, CK, Eckstein, EC, Donskey, CJ. Antianaerobic antibiotic therapy promotes overgrowth of antibiotic-resistant, gram-negative bacilli and vancomycin-resistant enterococci in the stool of colonized patients. Infect Control Hosp Epidemiol 2003;24:644649.
24.Paterson, DL, Ndirangu, M, Clarke, L, Bandlamuri, S, Donskey, CJ. Relative “collateral damage” caused by piperacillin/tazobactam and cefepime in patients treated in the intensive care unit. Presented at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy; September 14-17, 2003; Washington, DC. Abstract K-1418.
25.Thomas, C, Golledge, CL, Riley, TV. Ciprofloxacin and Clostridium difficile-associated diarrhea. Infect Control Hosp Epidemiol 2002;23:637638.
26.Wistrom, J, Norrby, SR, Myhre, EB, et al.Frequency of antibiotic-associated diarrhoea in 2,462 antibiotic-treated hospitalized patients: a prospective study. J Antimicrob Chemother 2001;47:4350.
27.Edlund, C, Nord, CE. Effect of quinolones on intestinal ecology. Drugs 1999;58(suppl 2):6570.
28.Harbarth, S, Cosgrove, S, Carmeli, Y. Effects of antibiotics on nosocomial epidemiology of vancomycin-resistant enterococci. Antimicrob Agents Chemother 2002;46:16191628.
29.Donskey, CJ, Helfand, MS, Pultz, NJ, Rice, LB. Effect of parenteral fluoroquinolone administration on persistence of vancomycin-resistant Enterococcus faecium in the mouse gastrointestinal tract. Antimicrob Agents Chemother 2004;48:326328.
30.Hecker, MT, Aron, DC, Patel, NP, Lehman, MK, Donskey, CJ. Unnecessary use of antimicrobials in hospitalized patients: current patterns of misuse with an emphasis on the antianaerobic spectrum of activity. Arch Intern Med 2003;163:972978.
31.Stiefel, U, Pultz, NJ, Harmoinen, J, Koski, P, Lindevall, K, Donskey, CJ. Oral administration of recombinant β-lactamase prevents piperacillin-induced overgrowth of nosocomial pathogens in the intestinal tract of mice. J Infect Dis 2003;188:16051609.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Infection Control & Hospital Epidemiology
  • ISSN: 0899-823X
  • EISSN: 1559-6834
  • URL: /core/journals/infection-control-and-hospital-epidemiology
Please enter your name
Please enter a valid email address
Who would you like to send this to? *


Altmetric attention score

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