Because of the widespread occurrence of resistance to sulfonamides among Enterobacteriaceae, some researchers have suggested using trimethoprim (TMP) alone instead of the combination sulfamethoxazole-trimethoprin (SMX-TMP) in treating infections with TMP-susceptible organisms. To answer whether SMX-TMP suppresses the emergence of resistant organisms compared with TMP alone, quantitative fecal cultures were made for total and TMP-resistant organisms before, during, and after SMX-TMP (800/160 mg twice a day) or TMP (200 or 100 mg twice a day) was given to 48 patients for 4 weeks in a prospective, randomized study. All three regimens left anaerobes intact and reduced the total aerobic coliform fecal flora by approximately 4 logs throughout the 4-week treatment period. In 11 of 19 (58%) patients taking TMP 200 mg twice daily, TMP-resistant organisms emerged or increased during therapy (P < 0.01, compared with none of the 12 controls), whereas in only 4 of 18 (22%) patients on SMX-TMP did TMP-resistant organisms increase. These TMP-resistant organisms increased by less than 1 log and were predominantly Pseudomonas and Acinetobacter species. In only one instance did an SMX-TMP-resistant Escherichia coli strain emerge after 4 weeks of SMX-TMP therapy. The slight increase in Pseudomonas and Acinetobacter species seen with TMP alone in this study raises a potential risk of giving TMP alone in settings where these organisms may cause senous infections, as in immunosuppressed patients.The drug combination sulfamethoxazole and trimethoprim (SMX-TMP) has come into increasing use in many situations. Because Enterobacteriaceae are often resistant to SMX but susceptible to TMP (3), some have suggested that TMP alone may be just as effective in treating many infections, such as acute, uncomplicated urinary tract infections (1, 9). However, concern has arisen that TMP alone may lead to increased resistance over that seen with the combination SMX-TMP. Gram-negative bacteria were shown by Reisberg et al. to develop resistance rapidly when exposed to increasing TMP concentrations in vitro (17). In 1968, Darrell and his co-workers also demonstrated that exposure to TMP in vitro produced increased resistance among Escherichia coli, Proteus, and Klebsiella. They also showed that TMP resistance emerged faster among sulfonamide-resistant strains exposed to SMX-TMP than among sulfonamide-susceptible organisms (4). Bushby, in 1971, reported in vitro data showing that the presence of SMX added to TMP reduced the emergence of TMP resistance among E. coli that were moderately susceptible to SMX (2), although he questioned whether the TMP-resistant strains that emerged with the TMP alone had reduced virulence on the basis of growth characteristics and alteration of 0 antigenicity. However, although 20 to 40% of Enterobacteriaceae are resistant to SMX and despite the widespread use of the combination SMX-TMP, little TMP resistance has emerged to date. Furthermore, recent studies have failed to reveal the emergence of increased resistance with l...