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JAC Advance Access published online on March 18, 2009
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkp050
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© The Author 2009. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Effect of long-term trimethoprim/sulfamethoxazole treatment on resistance and integron prevalence in the intestinal flora: a randomized, double-blind, placebo-controlled trial in children

Erwin L. van der Veen1,*, Anne G. M. Schilder1, Tim K. Timmers2, Maroeska M. Rovers1,3, Ad C. Fluit2, Marc J. Bonten2,3 and Maurine A. Leverstein-van Hall2

1 Department of Otorhinolaryngology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands 2 Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands 3 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands

Received 30 October 2008; returned 7 December 2008; revised 1 February 2009; accepted 2 February 2009

* Corresponding author. Tel: +31-302504580; Fax: +31-302505387; E-mail: E.L.vanderVeen{at}umcutrecht.nl

Objectives: The aim of this study was to test the hypothesis that trimethoprim/sulfamethoxazole selects for integron-positive and multidrug-resistant Enterobacteriaceae in the intestinal flora.

Methods: During 1 year of follow-up, antibiotic susceptibility and the presence of integrons were determined in faecal Enterobacteriaceae isolated from 99 children with chronic active otitis media, randomly assigned to treatment with trimethoprim/sulfamethoxazole or placebo (http://www.clinicaltrials.gov/; trial registration number NCT00189098 [ClinicalTrials.gov] ).

Results: At 6 and 12 weeks of follow-up, 32 (91%) and 24 (67%) children in the trimethoprim/sulfamethoxazole group carried trimethoprim/sulfamethoxazole-resistant Enterobacteriaceae versus 10 (21%) and 8 (17%) children in the placebo group [rate differences (RDs): 70 (95% CI: 55; 85) and 50 (95% CI: 31; 69)], respectively. Multiresistance also increased during trimethoprim/sulfamethoxazole treatment. At 6 weeks of follow-up, the integron prevalence was 26 (79%) in the trimethoprim/sulfamethoxazole group and 10 (22%) in the placebo group [RD: 57 (95% CI: 39; 75)]. After 12 weeks the integron prevalence, and after 1 year the susceptibility levels, had returned to baseline values.

Conclusions: Initially, trimethoprim/sulfamethoxazole usage was strongly associated with the appearance of integron-positive (multi)drug-resistant Enterobacteriaceae in the intestinal flora. After prolonged exposure to trimethoprim/sulfamethoxazole, however, this population of Enterobacteriaceae was substituted by a population with non-integron-associated resistance mechanisms. After trimethoprim/sulfamethoxazole was discontinued, susceptibility rates to all antibiotics returned to baseline levels.

Key Words: drug resistance , Enterobacteriaceae , intestine


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