The therapeutic efficacy of orally administered zidovudine (3'-azido-3'-deoxythymidine) was determined in animals infected with Escherichia coli and Salmonella dublin. The 50% effective dose (ED50) of zidovudine (9.6 to 11.8 mg/kg of body weight) compared favorably with that of trimethoprim (19.4 to 22.2 mg/kg) in mice with systemic E. coli infection. At 50 mg/kg, both zidovudine and ampicillin reduced the number of bacteria in the kidneys of mice and prevented lethal infection in mice with ascending pyelonephritis caused by E. coli. Zidovudine prevented a lethal S. dublin infection in calves over a wide dose range (8.0 to 31.0 mg/kg per day). Zidovudine levels in plasma of uninfected mice were 28.2 ± 4.5 and 7.9 ± 2.2 ,ug/ml at 30 and 60 min, respectively, exceeding the MICs for the bacteria used in the infections. Few zidovudine-resistant strains were observed. The in vivo data raise the possibility that zidovudine may have an antibacterial effect in patients receiving this therapy.The synthetic nucleoside zidovudine (3'-azido-3'-deoxythymidine) is an antimicrobial agent with a spectrum of in vitro activity that encompasses human immunodeficiency virus (HIV) (8) AIDS, abstr. no. 556, 1985), and gram-negative bacteria, including Escherichia coli, Klebsiella pneumoniae, Salmonella typhimurium, and Haemophilus influenzae (1). Zidovudine has shown no activity against Pseudomonas aeruginosa, grampositive or anaerobic bacteria, or common pathogenic fungi (such as Pneumocystis carinii) frequently isolated from HIV-infected patients (Nusinoff-Lehrman et al., Int. Conf. AIDS, 1985). E. coli and Salmonella dublin have been shown to be exquisitely susceptible to zidovudine, with in vitro MICs in the range of 0.0025 to 0.3 ,xg/ml (Table 1).We extended these in vitro observations to determine the in vivo efficacy of zidovudine in experimental bacterial infections that included a mouse systemic E. coli infection, acute ascending E. coli pyelonephritis in mice, and S. dublin salmonellosis in calves.MATERIALS AND METHODS Antimicrobial agents. Zidovudine and trimethoprim were laboratory reference preparations (Burroughs Wellcome Co., Research Triangle Park, N.C.). Ampicillin was purchased as the sodium salt (Sigma Chemical Co., St. Louis, Mo.). For all studies on mice, compounds were dissolved or suspended just before use in an aqueous suspending vehicle consisting of 1.0% Tween 80 and 0.5% low-viscosity sodium carboxymethylcellulose (Sigma). For studies in calves, zidovudine was administered by subcutaneous injection in an aqeuous solution of 20% dimethylformamide.Bacteria. The bacteria used for animal infections were veterinary and clinical isolates previously found to exhibit susceptibility in vitro to zidovudine and the reference antimicrobial agents used in this study. E. coli P855, used for the mouse systemic infection studies, is a clone from E. coli CN348 (isolated from a sick calf) maintained in the Well-* Corresponding author.come Research Laboratories strain collection. E. coli J96 was used for the mouse ascendin...