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.
OBJECTIVE
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).


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.
van der Veen
Erwin L
EL
Department of Otorhinolaryngology, Wilhelmina Children's Hospital, University Medical Center Utrecht, The Netherlands. E.L.vanderVeen@umcutrecht.nl
Schilder
Anne G M
AG
Timmers
Tim K
TK
Rovers
Maroeska M
MM
Fluit
Ad C
AC
Bonten
Marc J
MJ
Leverstein-van Hall
Maurine A
MA
D002648:Child; D002675:Child, Preschool; D004311:Double-Blind Method; D024901:Drug Resistance, Multiple, Bacterial; D004755:Enterobacteriaceae / Q000187:drug effects* / Q000235:genetics; D005500:Follow-Up Studies; D041981:Gastrointestinal Tract / Q000382:microbiology*; D006801:Humans; D007223:Infant; D032023:Integrons; D010033:Otitis Media / Q000188:drug therapy*; D015995:Prevalence; D012641:Selection, Genetic; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000627:therapeutic use*
D015662:Trimethoprim, Sulfamethoxazole Drug Combination