Trimethoprim/sulfametrole: evaluation of the available clinical and pharmacokinetic/pharmacodynamic evidence

Emergence of resistance to widely used trimethoprim/sulfamethoxazole (TMP/SMX) as well as common adverse events in human immunodeficiency virus (HIV)-infected patients casts interest on combinations of TMP with other sulfonamides. Sulfametrole (SMT) combined with TMP could provide a choice for difficult-to-treat infections, particularly when administered intravenously. The objective of this review was to evaluate the available clinical and pharmacokinetic/pharmacodynamic (PK/PD) evidence regarding TMP/SMT, particularly in comparison with TMP/SMX. We reviewed the available evidence retrieved from searches in PubMed/Scopus/Google Scholar and by bibliography hand-searching. In total, 46 eligible studies (most published before 1997) were identified, 7 regarding intravenous (i.v.) TMP/SMT, 24 regarding oral TMP/SMT and 15 providing comparative data for TMP/SMT versus TMP/SMX. The antimicrobial activity of TMP/SMT was similar to TMP/SMX for Gram-positive isolates. A greater percentage of Escherichia coli and Proteus spp. isolates were susceptible to TMP/SMT compared with TMP/SMX. PK/PD data suggest a dosage adjustment of i.v. TMP/SMT in patients with seriously impaired renal function. Four randomised controlled trials and 16 non-comparative studies reported good effectiveness/safety outcomes for oral TMP/SMT in genital ulcers (mainly chancroid), respiratory tract infections and urinary tract infections (UTIs). Moreover, i.v. TMP/SMT was effective against Pneumocystis jiroveci Infection in HIV-infected patients, severe pneumonia and UTIs. In one study, hypersensitivity reactions occurred in 18/52 (34.6%) of HIV-infected patients; 2/52 (3.8%) developed psychosis. Gastrointestinal adverse events were mild and rare. Excipients in i.v. TMP/SMT formulations might be less toxic compared with i.v. TMP/SMX formulations, particularly for children. In conclusion, despite the scarcity of contemporary evidence, available data suggest that TMP/SMT could be an alternative treatment option to TMP/SMX, even in serious infections, when administered intravenously.