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Background  Macrolide antibiotics are commonly administered for bacterial respiratory illnesses. Azithromycin (Az) is especially noted for extremely high intracellular concentrations achieved within macrophages which is far greater than the serum concentration. Clinical strains of Type B  Francisella  ( F. )  tularensis  have been reported to be resistant to Az, however our laboratory  Francisella  strains were found to be sensitive. We hypothesized that different strains/species of  Francisella  (including Type A) may have different susceptibilities to Az, a widely used and well-tolerated antibiotic.    Results   In vitro  susceptibility testing of Az confirmed that  F. tularensis subsp. holarctica  Live Vaccine Strain (LVS) (Type B) was not sensitive while  F. philomiragia, F. novicida , and Type A  F. tularensis  (NIH B38 and Schu S4 strain) were susceptible. In J774A.1 mouse macrophage cells infected with  F. philomiragia, F. novicida , and  F. tularensis  LVS, 5 μg/ml Az applied extracellularly eliminated intracellular  Francisella  infections. A concentration of 25 μg/ml Az was required for  Francisella- infected A549 human lung epithelial cells, suggesting that macrophages are more effective at concentrating Az than epithelial cells. Mutants of RND efflux components ( tolC  and  ftlC ) in  F. novicida  demonstrated less sensitivity to Az by MIC than the parental strain, but the  tolC  disc-inhibition assay demonstrated increased sensitivity, indicating a complex role for the outer-membrane transporter. Mutants of  acrA  and  acrB  mutants were less sensitive to Az than the parental strain, suggesting that AcrAB is not critical for the efflux of Az in  F. novicida . In contrast,  F. tularensis  Schu S4 mutants Δ acrB  and Δ acrA  were more sensitive than the parental strain, indicating that the AcrAB may be important for Az efflux in  F. tularensis  Schu S4.  F. novicida  LPS O-antigen mutants ( wbtN, wbtE, wbtQ  and  wbtA ) were found to be less sensitive  in vitro  to Az compared to the wild-type. Az treatment prolonged the survival of  Galleria  ( G .)  mellonella  infected with  Francisella .    Conclusion  These studies demonstrate that Type A  Francisella  strains, as well as  F. novicida  and  F. philomiragia , are sensitive to Az  in vitro. Francisella  LPS and the RND efflux pump may play a role in Az sensitivity. Az also has antimicrobial activity against intracellular  Francisella , suggesting that the intracellular concentration of Az is high enough to be effective against multiple strains/species of  Francisella , especially in macrophages. Az treatment prolonged survival an  in vivo  model of  Francisella- infection.

Azithromycin effectiveness against intracellular infections of Francisella