The conditions necessary for studies of the cross-resistance of tubercle bacilli (Mycobacterium tuberculosis) are discussed in the present paper.
1) Strains should be derived from single colonies. This is the most important, basic conditionto obtain clear-cut results. Use of mixtures of sensitive and resistant organisms or of resistantorganisms of different phenotypes may lead to misunderstanding of the nature of cross-resistance.
2) The degree of resistance (phenotype) should be estimated by a most sensitive method, forexample “actual count method” (Tsukamura, M.: Med. & Biol., 49: 87, 1958; Jap. J. Tuberc., 12: 46, 1964; Canetti, G. et al.: Bull. Int. Un. Tuberc., 37: 185, 1966). The method for estimatingthe phenotype may be changed according to the purpose of studies. In order to deal with a largedifference of the resistance, a non-quantitative method may be used, whereas, to deal with a littledifference, the “actual count method” must be used. The “actual count method” is a method in which the degree of resistance is estimated by the highest concentration of a drug in which 20 to 50 (if this is unavailable, 10 to 100) viable organisms are able to grow.
3) Sensitive organisms are defined as a population which is not exposed to any drug previouslyor a population which shows the same phenotype as the above population, and resistant organismsare defined as resistant mutants which retain heritably resistant properties. Unheritable resistantproperties are due to the phenomenon of “pseudoresistance”; the use of heavy inoculation makesvisible residual growth of sensitive organisms.
4) Cross-resistance studies should be done on different phenotypes. The number of resistantphenotypes of M. tuberculosis (H37Rv) remains usually a few.
5) From descriptive convenience, the cross-resistance was divided into the following categories: (1) complete cross-resistance (Resistant organisms selected by a drug A are resistant to drugs Aand B, and those selected by a drug B are also resistant to both drugs); (2) one-way crossresistance (Resistant organisms selected by a drug A are resistant to drugs A and B, but thoseselected by a drug B are resistant to only the drug B); (3) “major” cross-resistance (Resistantorganisms selected by a drug A are resistant to another drug B, and the increase of resistance toa drug B is more than ten-times when compared with the degree of resistance of the parentstrain); (4) “minor” cross-resistance (Resistant organisms selected by a drug A are resistant to adrug B, and the increase of resistance to the drug B is less than five-times when comparedwith the degree of resistance of the parent strain).
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