Chapter 10 



Development of Resistance 



Natural and Acquired Resistance 



The problem of increased bacterial resist- 

 ance to chemotherapeutic agents has been 

 the focus of special attention in recent years, 

 with increasing utilization of antibiotics for 

 the control of a variety of bacterial infec- 

 tions. The first two important antibiotics, 

 penicillin and streptomycin, have proved to 

 be of particular interest. They are similar 

 in some respects and different in others. Both 

 act primarily upon bacteria, have little 

 effect upon intracellular parasites (rickett- 

 siae), and act not at all or to only a very 

 limited extent upon fungi. They differ, how- 

 ever, in their respective antibacterial spectra. 

 Penicillin is active largely against cocci, 

 gram-positive aerobes and' anaerobes, and 

 spirochetes, but has only a limited effect 

 upon gram-negative rods and acid-fast bac- 

 teria unless used at high concentrations. 

 Streptomycin, on the other hand, is effective 

 against both gram-negati\'e and gram-posi- 

 tive bacteria, including the acid-fast organ- 

 isms, and is relatively less active against the 

 cocci and spirochetes than is penicillin. 

 Bacteria develop resistance to streptomycin 

 much more rapidly than to penicillin and 

 may lose that resistance much more slowly 

 (Finland, 1956). 



Different strains of the same species ex- 

 hibit considerable variation in their sensi- 

 tivity to a given antibiotic. Staphylococci 

 show wide ranges of sensitivity to penicillin. 

 The sensitivity of Mycobacterium tubercu- 

 losis to streptomycin ranges from 0.1 to 12.5 

 /xg per ml, or 1 to 125. This natural variation 



in sensitivity of a given organism is of great 

 practical importance from a chemotherapeu- 

 tic point of view, since it influences the 

 selection of the particular antibiotic for the 

 treatment of a given infection, and the con- 

 centrations to be used. 



In addition to the natural variation in 

 sensitivity, a population of organisms origi- 

 nally sensitive becomes gradually more 

 resistant or "fast" to a given antibiotic on 

 continued contact with it, either in the test 

 tube or in the body of the host. This phe- 

 nomenon is not new in either bacteriology 

 or chemotherapy. It has long been observed, 

 for example, that upon repeated administra- 

 tion of a drug, the infecting organism be- 

 comes less susceptible to it. This decrease 

 in sensitivity has been assumed to be of two 

 kinds: (1) a reduction of the sensitive strains 

 with a selection of the naturally resistant 

 forms; (2) a change of the sensitive strains 

 into resistant ones. 



Ehrlich and others reported, for example, 

 that the resistance of trypanosomes to atoxyl 

 and to dyes could l)e raised by gradut^lly 

 increasing the doses of the drug. A microbial 

 strain resistant to one type of compound 

 could still be sensitive to other agents. The 

 same organism could be made to develop 

 resistance against several substances, by a 

 series of treatments or adaptations. The 

 ability of various bacteria to become resist- 

 ant to sulfa drugs has also been well demon- 

 strated. When the bacteria are removed 

 from contact with the drug they become 

 sensitive again; the rate of loss of resistance 



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