Intracellular activity of zidovudine (3'-azido-3'-deoxythymidine, AZT) against Salmonella typhimurium in the macrophage cell line J774-2

Abstract

The antibacterial effect of zidovudine (AZT) has been demonstrated both in vitro and in vivo with experimental models of gram-negative bacterial infections. It has been associated with the absence or low occurrence of nontyphoid SalmoneUla infections in AIDS patients treated with AZT. Using the macrophage cell line J774-2, we demonstrate the inhibition of intracellular growth of Salmonella typhimurium by AZT. This effect is obtained with one-half of the MIC (1 ,ug/ml) of AZT for S. typhimurium. Inhibition of intracellular growth is observed after 4 h of incubation and persists at 24 h. Maximal inhibition is shown at a concentration of 128 ,ug/ml, and no further effect is observed with higher concentrations. When the inhibitory effect of AZT is compared with that of pefloxacin or that of ceftriaxone at half their MICs (0.2 and 0.02 ,ug/ml, respectively), AZT and pefloxacin give better results than ceftriaxone. In this study, using an intracellular model, we show that AZT is able to inhibit the intracellular multiplication of S. typhimurium at a minimal effective concentration lower than the MIC, indicating its potential for antibacterial accumulation in the macrophages.

Azidothymidine Produces Synergistic Activity in Combination with Colistin against Antibiotic-Resistant Enterobacteriaceae

“…dosing produced an area under the concentration-time curve (AUC) of 0.0014 mg • h/liter and a maximum concentration of drug in serum (C max ) of 0.0015 mg/liter while a 200-mg oral dosing gave rise to an AUC of 0.0017 mg • h/liter and a C max of 0.0018 mg/liter (35). AZT has been shown to be active against Gram-negative bacteria (18)(19)(20), but it is not known if the concentrations used clinically are sufficient to treat bacterial infections in humans. Colistin is effective against multidrug-resistant but colistin-susceptible Pseudomonas aeruginosa, K. pneumoniae, and Acinetobacter (36) strains and importantly against NDM-1-carrying Enterobacteriaceae (8).…”

“…It inhibits viral reverse transcriptase and was the first effective treatment for HIV/AIDS (17) entering the U.S. market in 1986. AZT is also active against Gram-negative bacteria (18)(19)(20)(21)(22) but has not been developed or approved for that purpose. It is thought to inhibit bacterial DNA replication by chain termination.…”

In vitro activities of nucleoside analog antiviral agents against salmonellae

“…These results suggest that ZDV, which has activity against salmonellae within macrophages (13), may play a role in the suppression of salmonellosis in patients infected with HIV, although microbial resistance can develop. Despite the fact that cross-resistance was not demonstrated, ddC and ddI at currently used dosages would not be expected to have clinical usefulness in the treatment or prevention of Salmonella infections.…”

“…Despite adequate antibacterial therapy, frequent relapses have been reported (32). It has been suggested that the recent decrease in frequency of human immunodeficiency virus (HIV)-associated Salmonella bacteremia may be attributable to the widespread use of ZDV (6,13,31). Increasingly, other nucleoside analogs, such as 2',3'-dideoxyinosine (ddI; didanosine) and 2',3'-dideoxycytidine (ddC; zalcitabine), which have undefined anti-Salmonella activity, are being used in the treatment of HIV infection.…”

“…Zidovudine (ZDV; 3'-azido-2',3'-dideoxythymidine) also has potent in vitro antibacterial activity against many members of the family Enterobacteniaceae, including Salmonella species (11,17,23,31). Intracellular growth of Salmonella typhimunium within macrophages is inhibited by ZDV (13). Orally administered ZDV has been shown to be as effective in mice as ampicillin in the treatment of Eschenichia coli ascending pyelonephritis and at least as effective as trimethoprim in systemic E. coli infections (17), and subcutaneous ZDV prevents lethal Salmonella dublin infection in calves (17).…”