Abstract
Most strains of enterobacteria andPseudomonas aeruginosa produce chromosomally-determined Class Iβ-lactamases. When synthesized copiously these enzymes cause resistance to almost allβ-lactams, except imipenem and, sometimes, carbenicillin and tenocillin. Elevatedβ-lactamase production arises transiently, via induction, inPseudomonas aeruginosa andEnterobacter, Citrobacter, Morganella, indole-positiveProteus andSerratia spp. when these organisms are exposed toβ-lactams. Permanent high-level enzyme production arises via mutation, in the stably-derepressed mutants of these species. These mutants arise spontaneously at high frequency (10−5–10−8). Most early penicillins and first-generation cephalosporins are strong inducers of Class I enzymes at sub-inhibitory concentrations, as are cefoxitin and imipenem. Consequently their MICs reflect what lability these antibiotics have to inducibly-expressedβ-lactamase. Except with imipenem this lability usually is so great that the inducible enzyme causes clinical resistance. Although most other newer cephalosporins and ureidopenicillins are labile to the Class I enzymes they induce poorly below the MIC, and their lability is not reflected in resistance unless secondary inducers (e.g. cefoxitin or imipenem) are present. Although the weak inducer activity of these agents helps to maintain their activity against the inducible cells it renders the drugs highly selective for the pre-existing stably-derepressed mutants. Many cases have been reported where stably-derepressed mutants have overrun inducible populations of bacteria in patients undergoing therapy withβ-lactamase-labile weak inducers such as ureidopenicillin and third-generation cephalosporins.
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Richmond, M. H., Sykes, R. B.: Theβ-lactamases of gram-negative bacteria and their possible physiological role. Advances in Microbial Physiology 1973, 9: 31–88.
Sykes, R. B., Matthew, M.: Theβ-lactamases of gramnegative bacteria and their role in resistance toβ-lactam antibiotics. Journal of Antimicrobial Chemotherapy 1976, 2: 115–157.
Aspiotis, A., Cullmann, W., Dick, W., Stieglitz, M.: Inducibleβ-lactamases are principally responsible for the naturally occurring resistance towardsβ-lactam antibiotics inProteus vulgaris. Chemotherapy 1986, 32: 236–246.
Cullmann, W., Dalhoff, A., Dick, W.: Non-specific induction ofβ-lactamase inEnterobacter cloacae. Journal of General Microbiology 1984, 130: 1781–1786.
Sawai, T., Kanno, M., Tsukamoto, K.: Characterization of eightβ-lactamases of gram-negative bacteria. Journal of Bacteriology 1982, 152: 567–571.
Sanders, C. C.: Novel resistance selected by the new expanded-spectrum cephalosporins. Journal of Infectious Diseases 1983, 149: 585–589.
Then, R. L., Angehrn, P.: Trapping of non-hydrolyzable cephalosporins by cephalosporinases inEntercbacter cloacae andPseudomonas aeruginosa as a possible resistance mechanism. Antimicrobial Agents and Chemotherapy 1982, 21: 711–717.
Livermore, D. M.: Kinetics and significance of the activity f the Sabath and Abrahams'β-lactamaseof Pseudomonas aeruginosa against cefotaxime and cefsulodin. Journal of Antimicrobial Chemotherapy 1983, 11: 169–179.
Livermore, D. M.: Doβ-lactamases ‘trap’ cephalosporins? Journal of Antimicrobial Chemotherapy 1985, 15: 511–514.
Vu, H., Nikaido, H.: Role ofβ-lactam hydrolysis in the mechanism of resistance of aβ-lactamase-derepressedEnterobacter cloacae strain to expanded-spectrumβ-lactams. Antimicrobial Agents and Chemotherapy 1985, 27: 393–398.
Vu, H., Nikaido, H.: Role ofβ-lactam hydrolysis in the mechanism of resistance of aβ-lactamase-derepressedEnterobacter cloacae strain to expanded-spectrumβ-lactams. Antimicrobial Agents and Chemotherapy 1985, 27: 393–398.
Livermore, D. M., Yang, Y. J.: β-lactamase lability and inducer power of newerβ-lactam antibiotics in relation to their activity againstβ-lactamase inducibility mutants ofPseudomonas aeruginosa. Journal of Infectious Diseases 1987, 155: 775–782.
Bush, K., Freudenberger, J. S., Sykes, R. B.: Interactions of aztreonam and related monobactams with beta-lactamases from gram-negative bacteria. Antimicrobial Agents and Chemotherapy 1982, 22: 414–420.
Nordstrom, K., Sykes, R. B.: Induction kinetics ofβ-lactamase biosynthesis inPseudomonas aeruginosa. Antimicrobial Agents and Chemotherapy 1974, 6: 734–740.
Minami, S., Yotsuji, A., Inone, M., Mitsuhashi, S.: Induction ofβ-lactamase by variousβ-lactam antibiotics inEnterobacter cloacae. Antimicrobial Agents and Chemotherapy 1980, 18: 382–385.
Okonogi, K., Kuno, M., Higashide, E.: Induction of βlactamase inProteus vulgaris. Journal of General Microbiology 1986, 132: 143–150.
Lindberg, F., Westman, L., Normark, S.: Regulatory components inCitrobacter freundii AmpC, β-lactamase induction. Proceedings of the National Academy of Sciences USA 1985, 82: 4620–4624.
Rosselet, A., Zimmermann, W.: Mutants ofPseudomonas aeruginosa with impairedβ-lactamase inducibility and increased sensitivity toβ-lactam antibiotics. Journal of General Microbiology 1973, 76: 455–457.
Curds, N. A. C., Eisenstadt, R. L., Rudd, C., White, A. J.: Inducible type Iβ-lactamase of gram-negative bacteria and resistance toβ-lactam antibiotics. Journal of Antimicrobial Chemotherapy 1986, 17: 51–62.
Williams, J. D.: Activity of imipenem againstPseudomonas aeruginosa andBacteroides species. Reviews of Infectious Diseases 1985, 7: S417-S425.
Hashizume, T., Yamaguchi, A., Hirata, T., Sawai, T.: Kinetic studies on the inhibition ofProteus vulgaris, β-lactamase by imipenem. Antimicrobial Agents and Chemotherapy 1984, 25: 149–151.
Jacobs, J. Y., Livermore, D. M., Davy, K. W. M.:Pseudomonas aeruginosa, β-lactamase as a defence against azlocillin, mezlocillin and piperacillin. Journal of Antimicrobial Chemotherapy 1984, 14: 221–229.
Livermore, D. M., Williams, J. D., Davy, K. W. M.: Cephalosporins resistance inPseudomonas aeruginosa, with special reference to the proposed trapping of antibiotics by beta-lactamase. Chemioterapia 1985, 4: 28–35.
Graham, W. C., Medeiros, A. A.: Antagonism of carbenicillin by cephalosprins in gram-negative bacilli. In: Nelson, J. D., Grassi, C. (ed.): Current chemotherapy and infectious disease. American Society for Microbiology, Washington, DC, 1980, p. 489–491.
Hoffmann, T. A., Cleary, T. J., Bercuson, D. H.: Effects of inducible beta-lactamase and antimicrobial resistance upon activity of newer beta-lactam antibiotics againstPseudomonas aeruginosa. Journal of Antibiotics (Tokyo) 1981, 34: 1334–1340.
Cullmann, W., Dick, W.: Cefpirome (HR810): lack of selection of beta-lactamase overproducing variants. Journal of Antibiotics (Tokyo) 1985, 38: 912–919.
Dalhoff, A., Cullmann, W.: Specificity ofβ-lactamase induction inPseudomonas aeruginosa. Journal of Antimicrobial Chemotherapy 1984, 14: 349–357.
Tausk, F., Stratton, C. W.: Effect of clavulanic acid on the activity of ticarcillin againstPseudomonas aeruginosa. Antimicrobial Agents and Chemotherapy 1986, 30: 584–589.
Kasai, K.: Antibacterial antagonism ofβ-lactam antibiotics in experimental infections. Chemotherapy 1986, 32: 148–158.
Livermore, D. M.: Class 1β-lactamase expression inPseudomonas aeruginosa and cephalosporin resistance. Lancet 1986, i: 450.
Phillips, I.: Beta-lactamase induction and derepression. Lancet 1986, i: 801–802.
Williams, R. J., Livermore, D. M., Lindridge, M. A., Said, A. A., Williams, J. D.: Mechanisms of resistance toβ-lactam antibiotics in British isolates ofPseudomonas aeruginosa. Journal of Medical Microbiology 1984, 17: 283–293.
Gwynn, M. N., Rolinson, G.: Selection of variants of gram-negative bacteria with elevated production of type Iβ-lactamase. Journal of Antimicrobial Chemotherapy 1983, 11: 577–581.
Lindberg, F., Normark, S.: Contribution of chromosomalβ-lactamases toβ-lactam resistance in enterobacteria. Reviews of Infectious Diseases 1986, 8, Supplement 3: 292–304.
Wiedemann, B.: Genetic and biochemical basis of resistance ofEnterobacteriaceae toβ-lactam antibiotics. Journal of Antimicrobial Chemotherapy 1986, 18, Supplement B: 31–38.
Sanders, C. C., Sanders, W. E.: Type Iβ-lactamases of gram-negative bacteria: interactions withβ-lactam antibiotics. Journal of Infectious Diseases 1986, 154: 792–800.
Sanders, C. C., Sanders, W. E.: Microbial resistance to newer-generationβ-lactam antibiotics: clinical and laboratory implications. Journal of Infectious Diseases 1985, 151: 399–406.
Kirkpatrick, B., Ashby, J., Wise, R.: β-lactams and imipenem. Lancet 1986, i: 802.
Quinn, J. P., Dudek, E. J., Divencenzo, C. A., Lucks, D. A., Lerner, S. A.: Emergence of resistance to imipenem during therapy forPseudomonas aeruginosa infections. Journal of Infectious Diseases 1986, 154: 289–294.
Sanders, C. C., Sanders, W. E., Goering, R. V.: Influence of clindamycin on derepression ofβ-lactamasesin Enterobacter spp. andPseudomonas aeruginosa. Antimicrobial Agents and Chemotherapy 1983, 24: 48–53.
Noto, T., Miyakawa, S., Oishi, H., Endo, H., Okazaki, H.: Thiolactomycin, a new antibiotic. III: In vitro antibacterial activity. Journal of Antibiotics (Tokyo) 1982, 35: 401–410.
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Livermore, D.M. Clinical significance of beta-lactamase induction and stable derepression in gram-negative rods. Eur. J, Clin. Microbiol. 6, 439–445 (1987). https://doi.org/10.1007/BF02013107
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DOI: https://doi.org/10.1007/BF02013107