Mycobacteria as intracellular pathogens : current notions of pathogenicity, virulence and drug resistance and their relation to effective therapy

International audienceMost of the in vitro antimicrobial testing has been essentially deviced keeping in mind extracellular bacteria which relates not only on the in vitro MICs and MBCs of a drug, but also its pharmacokinetics. It is, therefore, a common practice to relate the in vitro activity of a drug to its serum level concentrations after a standard antibiotic dose has been given by an appropriate route, its half-life in the plasma, the degree of protein binding, and its concentrations in the tissues. The clinical criteria usually retained are the response of patients, clinically and microbiologically, after a drug regimen is given at appropriate standard dosage. It is, however, increasingly clear that the above approach must be modified in case of intracellular pathogens as intricate bacteria-phagocyte interactions may not only contribute to yet not fully understood factors contributing to the pathogenesis of the disease, but may also alter the expected response to therapy. In this context, not only the mechanisms of intracellular survival of such pathogens, but also their interaction with the host's immune system and the identification of factors able to modulate bacterial growth intracellularly as well as their effects at the level of intracellular pharmacokinetic and pharmacodynamic of a drug (or drug combinations) are yet to be investigated in detail. Keeping the above objectives in mind, the present paper attempts to clarify the mechanisms of mycobacterial pathogenicity at the molecular level by outlining the events following infection of macrophages, the role of mycobacterial cell envelope in mycobacterial virulence, pathogenicity and drug resistance, and the new strategies developed to circumvent the disease caused by multiple drug-resistant opportunist mycobacteria. In addition, present knowledge concerning extracellular and intracellular activities of drugs currently employed and those under investigation, the criteria established for in vitro drug activity testing as well as future prospects will be reviewed. For practical purposes we will consider "pathogenicity" as a property of a microbial species to cause infection and disease in man or experimental animals, whereas "virulence" will be considered as the severity of disease as caused by distinct strains within the same species