Use of aminoglycosides in treatment of infections due to intracellular bacteria.

Abstract

Soon after antibiotics were introduced into medical practice, authors pointed out that microorganisms capable of surviving within phagocytic cells may be protected from the killing actions of antibiotics with a poor ability to cross the eukaryotic cell membrane, leading to therapy failures and disease relapses (86, 108). Following the pioneering work by Bonventre et al. (21) that showed that mouse peritoneal macrophages were impermeable to streptomycin in vitro, the aminoglycosides have been included in such a category. Failure of streptomycin and other aminoglycosides to treat infections due to strict or facultative intracellular pathogens (e.g., rickettsial diseases, chlamydial diseases, and typhoid fever) have reinforced this point of view. Also, in vitro infected cell systems have been developed to test the activities of antibiotics against intracellular pathogens, and in many instances they have shown the limited intracellular activity of aminoglycosides compared to their strong bactericidal potential in extracellular medium (52, 92). However, at the same time, streptomycin was successfully used to treat infections due to facultative intracellular pathogens, such as tuberculosis (especially tuberculous meningitis) (120), plague (133), brucellosis (160), or tularemia (55). As for tuberculosis, clinical data were concordant with the demonstration by Mackaness et al. (106) that streptomycin could inhibit growth of Mycobacterium tuberculosis within macrophages. Both these clinical and experimental data have been overlooked for several decades. Later experiments by Tulkens et al. (22, 179) have confirmed that aminoglycosides are readily incorporated into phagocytes when these cells are in contact with the antibiotic for prolonged periods (i.e., more than 24 h). The present review deals with the potential role of aminoglycosides, and especially streptomycin, in the antibiotic therapy of infections due to intracellular pathogens. Our goal is to highlight the concept that categorization of aminoglycosides as strictly ineffective against intracellular pathogens is in some ways too simplistic and does not correspond to clinical experience, since aminoglycosides remain in fact a “gold standard” therapy in a number of infections due to intracellularly surviving pathogens.