, Volume 22, Supplement 2, pp S105–S110 | Cite as

In vitro stepwise selection of resistance to quinolones, β-lactams and amikacin in nosocomial gram-negative bacilli

  • M. Michéa-Hamzehpour
  • Anneliese Kahr
  • J. -C. Pechère


The ability of six antibiotics to produce resistance by stepwise selection on agar medium was assessed in 24 gram-negative rods.Escherichia coli was the strain least prone to selection of resistance, whereasPseudomonas aeruginosa frequently developed resistance to all antibiotics. When used alone, ciprofloxacin, pefloxacin, amikacin, ceftazidime and cefpirome were associated with a comparable risk of acquired resistance (in 14 to 17 out of 24 strains); imipenem selected resistant strains in 10/24 isolates (5/18 in non-pseudomonas strains). The number of strains exhibiting cross resistance with structurally unrelated antibiotics was 11 after pefloxacin treatment, eight after exposure to ciprofloxacin, six after ceftazidime, and one after imipenem or cefpirome. The combination of ciprofloxacin with amikacin was less efficient in reducing acquisition of resistance than the combination of ciprofloxacin with a beta-lactam: ciprofloxacin plus cefpirome was especially potent in this respect.


Quinolones Ceftazidime Amikacin Imipenem Pefloxacin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Schrittweise Selektion der Resistenz gegenüber Chinolonen, β-Laktam-Antibiotika und Amikacin bei gramnegativen Erregern nosokomialer Infektionen


Durch die schrittweise Selektion auf Agarmedium wurde die Fähigkeit von sechs Antibiotika zur Induktion von Resistenz bei 24 gramnegativen Stäbchen geprüft. BeiEscherichia coli war die Resistenzentwicklung durch Selektion weniger ausgeprägt,Pseudomonas aeruginosa hatte hingegen eine ausgeprägte Neigung zur Resistenzentwicklung gegen alle getesteten Antibiotika. Bei Einsatz als Einzelsubstanzen waren Ciprofloxacin, Pefloxacin, Amikacin, Ceftazidim und Cefpirom mit einem vergleichbaren Risiko erworbener Resistenz (bei 14 bis 17 von 24 der getesteten Stämme) assoziiert. Imipenem selektierte resistente Stämme von 10 der 24 Isolate (5/18 der Nicht-Pseudomonas-Stämme). Nach Behandlung mit Pefloxacin entwickelten 11 Stämme eine Kreuzresistenz mit strukturell unverwandten Antibiotika; nach Exposition gegenüber Ciprofloxacin waren es acht, nach Ceftazidim sechs und nach Imipenem oder Cefpirom einer. Die Kombination von Ciprofloxacin mit Amikacin hatte weniger Potential, die Resistenzentwicklung zu verhindern als die Kombination von Ciprofloxacin mit einem β-Laktam-Antibiotikum. Ciproflox-acin plus Cefpirom war in dieser Hinsicht besonders wirksam.


  1. 1.
    Gibbons, A. Exploring new strategies to fight drug-resistant microbes. Science 257 (1992) 1036–1038.PubMedGoogle Scholar
  2. 2.
    Michéa-Hamzehpour, M., Auckenthaler, R., Regamey, P., Pechère, J. C. Resistance occurring after fluoroquinolone therapy of experimentalPseudomonas aeruginosa peritonitis. Antimicrob. Agents Chemother. 31 (1987) 1803–1808.PubMedGoogle Scholar
  3. 3.
    Chin, N. X., Clynes, N., Neu, H. C. Resistance to ciprofloxacin appearing during therapy. Am. J. Med. 87 (Suppl. 5A) (1989) 28S-31S.Google Scholar
  4. 4.
    Gutmann, L., Williamson, R., Moreau, N., Kitzis, M. D., Collatz, E., Acar, J. F., Goldstein, F. W. Cross resistance to nalidixic acid, trimethoprim, and chloramphenicol associated with alterations in outer membrane proteins ofKlebsiella, Enterobacter andSerratia. J. Infect. Dis. 151 (1985) 501–507.PubMedGoogle Scholar
  5. 5.
    Bryson, L., Szybalski, W. Microbial selection. Science 116 (1952) 45–51.Google Scholar
  6. 6.
    Michéa-Hamzehpour, M., Pechère, J. C., Marchou, B., Auckenthaler, R. Combination therapy: a way to limit emergence of resistance? Am. J. Med. 80 (Suppl. 6B) (1986) 138–142.PubMedGoogle Scholar
  7. 7.
    Thornsberry, C., Anhalt, J., Barry, A. L., Gerlach, E. H., Hossom, J., Jones, R. N., Matsen, J. M., Moellering, R. C., Norton, R. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. National Committee for Clinical Laboratory Standards, Villanova, PA, vol. 3 1983, pp. 48–56.Google Scholar
  8. 8.
    Milatovic, D., Braveny, I. Development of resistance during antibiotic therapy. Eur. J. Clin. Microbiol. 6 (1987) 234–244.PubMedGoogle Scholar
  9. 9.
    Michéa-Hamzehpour, M., Auckenthaler, R., Kunz, J., Pechère, J. C. Effect of a single dose of cefotaxime or ceftriaxone on human faecal flora. A double-blind study. Drugs 35 (Suppl. 2) (1988) 6–11.Google Scholar
  10. 10.
    Sanders, C. C., Sanders, Jr. W. E., Goering, R. V., Werner, V. Selection of multiple antibiotic resistance by quinolones, β-lactams, and aminoglycosides with special reference to cross-resistance between unrelated drug classes. Antimicrob. Agents Chemother. 26 (1984) 797–801.PubMedGoogle Scholar
  11. 11.
    Ubukata, K., Nonoguchi, R., Matsuhashi, M., Song, M. D., Konno, M. Restriction maps of the regions coding for methicillin and tobramycin resistances on chromosomal DNA in methicillin-resistant staphylococci. Antimicrob. Agents Chemother. 33 (1989) 1624–1626.PubMedGoogle Scholar
  12. 12.
    Shalit, I., Berger, S. A., Gorea, A., Frimerman, H. Widespread quinolone resistance among methicillin-resistantStaphylococcus aureus isolated in a general hospital. Antimicrob. Agents Chemother. 33 (1989) 593–594.PubMedGoogle Scholar
  13. 13.
    Blumberg, H. M., Rimland, D., Carroll, D. J., Terry, P., Wachsmuth, I. K. Rapid development of ciprofloxacin resistance in methicillin-susceptible and -resistantStaphylococcus aureus. J. Infect. Dis. 163 (1991) 1279–1285.Google Scholar
  14. 14.
    Hori, S., Ohshita, Y., Utsui, Y., Hiramatsu, K. Sequential acquisition of norfloxacin and ofloxacin resistance by methicillin-resistant and -susceptibleStaphylococcus aureus. Antimicrob. Agents Chemother. 37 (1993) 2278–2284.PubMedGoogle Scholar
  15. 15.
    Cohen, S. P., McMurry, L. M., Hooper, D. C., Wolfson, J. S., Levy, S. B. Cross-resistance to fluoroquinolones in multiple-antibiotic-resistant (Mar)Escherichia coli selected by tetracycline or chloramphenicol: decreased drug accumulation associated with membrane changes in addition to OmpF reduction. Antimicrob. Agents Chemother. 33 (1989) 1318–1325.PubMedGoogle Scholar
  16. 16.
    Michéa-Hamzehpour, M., Lucain, C., Pechère, J. C. Resistance to pefloxacin inPseudomonas aeruginosa. Antimicrob. Agents Chemother. 35 (1991) 512–518.PubMedGoogle Scholar
  17. 17.
    Trias, J., Nikaido, H. Outer membrane protein D2 catalyzes facilitated diffusion of carbapenems and penems through the outer membrane ofPseudomonas aeruginosa. Antimicrob. Agents Chemother. 34 (1990) 52–57.PubMedGoogle Scholar
  18. 18.
    Jacobson, K. L., Cohen, S. H., King, J. H., Lippert, W. E., Inciardi, J. F., Iglesias, T.: The relationship between resistance to extended spectrum cephalosporins and antecedent antibiotic use in type 1 β-lactamase producing organisms. 33rd ICAAC, USA 1993, Abstract 625.Google Scholar
  19. 19.
    Wallrauch-Schwarz, C., Voss, A., Milatovic, D., Braveny, I.: Development of resistance to new β-lactams and ciprofloxacin during therapy study. A prospective study. 33rd ICAAC, USA 1993, Abstract 627.Google Scholar

Copyright information

© MMV Medizin Verlag GmbH München 1994

Authors and Affiliations

  • M. Michéa-Hamzehpour
    • 1
  • Anneliese Kahr
    • 1
  • J. -C. Pechère
    • 1
  1. 1.Dept. of Genetics and Microbiology, Centre Médical UniversitaireUniversity of GenevaSwitzerland

Personalised recommendations