106 



NATURE, FORMATION, AND ACTIVITIES 



most iiLstances this resistance was increased 

 gradually. However, in some cases, there was 

 a sudden increase in resistance of isolated 

 colonies from relatively low values to more 

 than 50,000 Mg per ml. When a culture of 

 organisms was made resistant by exposure 

 to streptomycin in broth, some of the cells 

 showed marked pleomorphism and in some 

 instances underwent changes in biochemical 

 reactions. However, when resistant organ- 

 isms were obtained from a patient during or 

 after treatment, no morphological or cultural 

 differences were observed, as compared with 

 the sensitive strains isolated from the same 

 patient. 



The development of resistance of fungi to 

 polyenic antifungal antibiotics has been 

 studied by Stout and Pagano (1955) and by 

 Pledger (1957). These authors showed that 

 by repeated transfer in the presence of poly- 

 enes the resistance of naturally sensitive 

 fimgi was only slightly increased. Pledger, 

 for instance, reported that after 15 to 38 

 transfers in the presence of candicidin, can- 

 didin, filipin, and nystatin, the resistance of 

 strains of ('. albicans and Sacch. ccrevisiae 

 increased only 1.5- to 8.8-fold. 



Mechanism of Development of Resist- 

 ance 



Various explanations have been suggested 

 for the development of resistance. These can 

 be summarized as follows: (1) Induced 

 resistance is due to the killing of sensitive 

 cells in a given bacterial population, which 

 permits the more resistant cells to grow 

 selectively. (2) The phenomenon of resist- 

 ance is due to the acquisition of new enzyme 

 systems or to new metabolic activities which 

 permit the organism to survive in spite of 

 the presence of the particular inhibiting 

 agent. (3) Certain treatments tend to reverse 

 the effect of resistance or to prevent its 

 occurrence altogether. 



Davies, Hinshelwood, and Pryce (1944) 

 expressed the above concepts of the develop- 



ment of adaptation of an organism to an 

 antibacterial agent as follows: (1) Adapta- 

 tion occurs by natural selection from an 

 initially heterogeneous population. (2) Adap- 

 tation occurs by the modification of the 

 individual cells, as a result of the establish- 

 ment in the cells of a mechanism alternative 

 to that normally in use, or to a quantitative 

 modification of the existing mechanism. (3) 

 Adaptation is a change in some center of 

 organization of the cell. When variations or 

 adaptive changes occur, there is an actual 

 modification of the character of the individ- 

 ual cells, although selection may be super- 

 imposed on this when modified and unmodi- 

 fied cells exist together. Postgate and 

 Hinshelwood (1946) found that most con- 

 sideration should be given to the hypothesis 

 that ciualitative and cjuantitative changes 

 occur in the cell enzymes in response to the 

 changed medium. 



The development of resistance among bac- 

 teria sensitive to particular antibiotics, on 

 contact with such antibiotics, is sometimes 

 highly specific; those bacteria that become 

 resistant to one antil)iotic may still remain 

 sensitive to another. Staphylococci which 

 develop resistance to penicillin are not 

 affected in their sensitivity to streptomycin 

 or to various other antibiotics. 



When an organism develops resistance to 

 one antibiotic and yet remains sensitive to 

 another, the modes of action of these two 

 compounds are assumed to be different. 

 According to Chain and Florey (1944), the 

 formation by a given organism of strains 

 resistant to dift'erent antibiotics serves to 

 emphasize "the great variety of ways hi 

 which the organization of the cell is open to 

 attack by chemical substances." 



Bryson and Demerec (1955) analyzed the 

 phenomenon of the de^'elopment of resist- 

 ance to drugs; this was considered to be an 

 important aspect of the continuing process 

 of microbial evolution. The use of anti- 

 biotics resulted in the selection of new types 



