DEVELOPMENT OF RESISTANCE 



111 



administered and also showed moderate to 

 marked resistance to the other one and to 

 neomycin. 



Finland (1958) also found cross-resistance 

 between kanamycin, paromomycin, and 

 neomycin, but little or none between these 

 and streptomycin. The fact that they all 

 show 8th cranial nerve toxicity and renal 

 toxicity was believed to indicate further the 

 relationship between chemical structure and 

 pharmacological properties. 



Welsch (1957), who examined the prol)- 

 lems of resistance facing the clinician, em- 

 phasized that the antibiotics should be used 

 with the utmost care. He concluded that 

 bacterial resistance takes place at three 

 different biological levels — the species, the 

 strain, and the individual cell — with different 

 clinical implications in each instance: 



1. Variations of resistance at the level of 

 the species account for the occurrence of 

 superinfections as the result of a selective 

 destruction of some organisms of the normal 

 flora. The clinician must thus make a first 

 approximation of the antibiotic spectrum of 

 the causative organism for emergency 

 therapeutics. 



2. Differences of resistance between natu- 

 ral strains within a given species are very 

 marked in staphylococci. The heterogeneity 

 of the species accounts for the results ob- 

 tained from the widespread use of an anti- 

 biotic, in the selection of resistant strains, 

 and the occurrence of resistant cross-infec- 

 tions in a treated individual. 



3. The occurrence of spontaneous mutants 

 accounts for variation of resistance among 

 individuals of a pure bacterial population. It 

 was suggested that environmental factors 

 might influence the phenotypic expression of 

 individual resistant mutants derived from 

 the same clone. This hypothesis is based on 

 the fact that the degree of resistance ob- 

 served is not necessarily quantitatively re- 

 lated to the concentration of the drug to 

 which the bacteria were submitted, ^'aria- 



tion of resistance at the level of the individ- 

 ual cell accounts for the progressive in- 

 effectiveness of chemotherapy sometimes 

 observed during treatment. The practical 

 importance of this type of resistance was said 

 to be limited largely to streptomycin therapy 

 and to treatment of tuberculosis. The use of 

 an association of chemotherapeutic agents is 

 known to minimize the emergence of resist- 

 ant organisms. 



Welsch further emphasized that organ- 

 isms surviving the bactericidal action of an 

 antibiotic need not necessarily be resistant 

 to the drug, as in the case of penicillin and 

 streptomycin. Further, exposure of l)acteria 

 to an association of antibiotics does not 

 necessarily prevent the emergence of resist- 

 ant individuals. 



Bacterial cultures with resistance acquired 

 in vitro show certain altered biological char- 

 acteristics, such as partial or complete 

 dependence on the antibiotic, decreased via- 

 bility, retarded growth rate, slower meta- 

 bolic reactions, decreased or altered nutri- 

 tional re(iuirements, certain pleomorphic 

 changes, changed cultural properties, 

 changed staining reactions, and frequently a 

 reduction in virulence. 



Bacterial cells made resistant to anti- 

 biotics grow at a lower rate and produce less 

 growth in simple and complex media than 

 do the original sensitive strains. When the 

 resistant strains are grow^n in the presence 

 of the sensitive parent strains but in the 

 absence of the corresponding antibiotic, the 

 former are suppressed, especially in simple 

 media. This was also recently established by 

 Blackwell and McVeigh (1960) hi their 

 study of the effect of dihydrostreptomycin 

 upon E. coll. 



Sevag and Rosanoff' (1952) demonstrated 

 that the synthesis of phenylalanine and as- 

 partic acid by sensitive cells of Staph, aureus 

 is blocked by streptomycin. These amino 

 acids are synthesized by both sensitive and 

 resistant cells in the absence of streptomycin. 



