In vitro effects of azithromycin on Salmonella typhi:: early inhibition by concentrations less than the MIC and reduction of MIC by alkaline pH and small inocula

To explain good clinical results of azithromycin in patients with typhoid fever, 10 strains of Salmonella typhi were grown in cation-adjusted Mueller-Hinton broth. MICs of azithromycin were 4-16 mg/L. At a sub-MIC of 2 mg/L, early inhibition of growth was shown at 2, 4 and 8 h of incubation, but at 24 and 48 h growth to turbidity occurred. At 4 mg/L, inhibition occurred up to 8 h, after which growth towards turbidity followed. Elongated curved bacilli formed in broth containing 4 mg/L after 24-48 h. Adjusting the pH of the broth with phosphate-citrate buffer to 7.5 and 8.0 caused reductions in MICs to 0.25-0.5 mg/L. Large inocula of 10(6) cfu/mL resulted in median MICs four- to six-fold greater than with inocula of 10(1)-10(3) cfu/mL. An inoculum of 10 bacteria per mt in broth at pH 7.5 resulted in an MIC of 0.13 mg/L. Clinical benefits in patients may occur because of early inhibition by sub-MIC concentrations of azithromycin, and due to lower MICs at alkaline pH and lower MICs with small inocula that may correspond to the low-grade bacteraemia in typhoid fever.