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Aminoglycoside Adaptive Resistance

Importance for Effective Dosage Regimens

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Abstract

There are various pharmacodynamic features of the aminoglycosides that are thought to contribute to the benefits of once-daily administration, of which the ability to induce adaptive resistance is the least understood and discussed. However, this may be the most important characteristic conferring increased efficacy with extended interval dose administration. Adaptive resistance describes a reversible refractoriness to the bactericidal effect of an antibacterial agent. It is well documented for the aminoglycosides but has also been seen with the quinolones. It does not appear to be caused by a genetic mutational change but rather by a protective phenotypic alteration in bacterial characteristics. This includes reversible down-regulation of the active transport of aminoglycosides into Gram-negative bacteria.

In vitro, animal and clinical studies have shown that marked adaptive resistance of Gram-negative bacteria to aminoglycosides occurs within 1-2 hours of the first dose. The duration of adaptive resistance relates directly to the half-life of elimination of the aminoglycoside. With normal human aminoglycoside pharmacokinetics, the resistance may be maximal for up to 16 hours after a single dose of aminoglycoside, followed by partial return of bacterial susceptibility at 24 hours and complete recovery at around 40 hours. With conventional dosage regimens, second and subsequent doses of aminoglycoside are given at the time of maximal resistance and this practice is also likely to reinforce the resistance. Dose administration at 24 hour intervals, or longer, may increase efficacy by allowing time for adaptive resistance to reverse.

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References

  1. Barclay ML, Kirkpatrick CMJ, Begg EJ. Once-daily aminoglycoside therapy: is it less toxic than multiple daily doses and how should it be monitored? Clin Pharmacokinet 1999; 36: 89–98

    Article  PubMed  CAS  Google Scholar 

  2. Barclay ML, Begg EJ, Chambers ST. Adaptive resistance following single doses of gentamicin in a dynamic in vitro model. Antimicrob Agents Chemother 1992; 36: 1951–7

    Article  PubMed  CAS  Google Scholar 

  3. Daikos GL, Jackson GG, Lolans VT, et al. Adaptive resistance to aminoglycoside antibiotics from first-exposure down-regulation. J Infect Dis 1990; 162: 414–20

    Article  PubMed  CAS  Google Scholar 

  4. Karlowsky JA, Saunders M, Harding GAJ, et al. In vitro characterisation of aminoglycoside adaptive resistance in Pseudomonas aeruginosa. Antimicrob Agents Chemother 1996; 40: 1387–93

    PubMed  CAS  Google Scholar 

  5. Korvick JA, Yu VL. Antimicrobial agent therapy for Pseudomonas aeruginosa. Antimicrob Agents Chemother 1991; 35: 2167–72

    Article  PubMed  CAS  Google Scholar 

  6. Gould IM, Milne K, Jason C. Concentration-dependent bacterial killing, adaptive resistance and post-antibiotic effect of ciprofloxacin alone and in combination with gentamicin. Drugs Exp Clin Res 1990; 16(12): 621–8

    PubMed  CAS  Google Scholar 

  7. Gould IM, Milne K, Harvey G, et al. Ionic binding, adaptive resistance and post-antibiotic effect of netilmicin and ciprofloxacin. J Antimicrob Chemother 1991; 27: 741–8

    Article  PubMed  CAS  Google Scholar 

  8. Chamberland S, Malouin F, Rabin HR, et al. Persistence of Pseudomonas aeruginosa during ciprofloxacin therapy of a cystic fibrosis patient: transient resistance to quinolones and protein F-deficiency. J Antimicrob Chemother 1990; 25: 995–1010

    Article  PubMed  CAS  Google Scholar 

  9. Gilleland LB, Gilleland HE, Gibson JA, et al. Adaptive resistance to aminoglycoside antibiotics in Pseudomonas aeruginosa. J Med Microbiol 1989; 29: 41–50

    Article  PubMed  CAS  Google Scholar 

  10. Bodey GP, Middleman E, Umsawadi T, et al. Intravenous gentamicin therapy for infections in patients with cancer. J Infect Dis 1971; Suppl. 124: S174-9

  11. Jackson GG, Riff LJ. Pseudomonas bacteremia: pharmacologic and other bases for failure of treatment with gentamicin. J Infect Dis 1971; 124 Suppl.: S185–91

    Article  PubMed  Google Scholar 

  12. Xiong YQ, Caillon J, Drugeon H, et al. The effect of rifampicin on adaptive resistance of Pseudomonas aeruginosa to aminoglycosides. J Antimicrob Chemother 1996; 37: 993–8

    Article  PubMed  CAS  Google Scholar 

  13. Barclay ML. Studies to optimise dosage regimens for aminoglycoside and other antibiotics [MD thesis]. Dunedin (NZ): University of Otago, 1995: 50–7

    Google Scholar 

  14. Barclay ML, Begg EJ, Chambers ST. The effect of aminoglycoside-induced adaptive resistance on the antibacterial activity of other antibiotics against Pseudomonas aeruginosa in vitro. J Antimicrob Chemother 1996; 38: 853–8

    Article  PubMed  CAS  Google Scholar 

  15. Daikos GL, Lolans VT, Jackson GG. First-exposure adaptive resistance to aminoglycosides in vivo with meaning for optimal clinical use. Antimicrob Agents Chemother 1991; 35: 117–23

    Article  PubMed  CAS  Google Scholar 

  16. Xiong Y-A, Caillon J, Kergueris MF, et al. Adaptive resistance of Pseudomonas aeruginosa and killing kinetics in a rabbit endocarditis model. Antimicrob Agents Chemother 1997; 41: 823–6

    PubMed  CAS  Google Scholar 

  17. Barclay ML, Begg EJ, Chambers ST, et al. Adaptive resistance to tobramycin in Pseudomonas aeruginosa in the sputum of patients with cystic fibrosis. J Antimicrob Chemother 1996; 37: 1155–64

    Article  PubMed  CAS  Google Scholar 

  18. Bryan LE, Van Der Elzen HM. Gentamicin accumulation by sensitive strains of Escherichia coli and Pseudomonas aeruginosa. J Antibiot 1975; 28: 696–703

    Article  PubMed  CAS  Google Scholar 

  19. Hancock REW. Aminoglycoside uptake and mode of action — with special reference to streptomycin and gentamicin. I. Antagonists and mutants. II. Effects of aminoglycosides on cells. J Antimicrob Chemother 1981; 8: 429–45

    Article  PubMed  CAS  Google Scholar 

  20. Hancock REW, Bell A. Antibiotic uptake into Gram-negative bacteria. In: Jackson GG, editor. Perspectives in antiinfective therapy. Braunschweig (FRG): Vieweg and Sohn, 1989: 21–8

    Google Scholar 

  21. Jackson GG, Lolans VT, Daikos GJ. The inductive role of ionic binding in the bactericidal and postexposure effects of aminoglycoside antibiotics with implications for dosing. J Infect Dis 1990; 162: 408–13

    Article  PubMed  CAS  Google Scholar 

  22. Gilbert DN. Aminoglycosides. In: Mandell GL, Bennett JE, Dolin R, editors. Principles and practice of infectious diseases. 4th ed. New York: Churchill Livingstone, 1995: 279–306

    Google Scholar 

  23. Peterson AA, Hancock REW, McGroarty EJ. Binding of polycationic antibiotics and polyamines to lipopolysaccharides of Pseudomonas aeruginosa. J Bacteriol 1985; 164: 1256–61

    PubMed  CAS  Google Scholar 

  24. Bryan LE, Kwan S. Roles of ribosomal binding, membrane potential and electron transport in bacterial uptake of streptomycin and gentamicin. Antimicrob Agents Chemother 1983; 23: 835–45

    Article  PubMed  CAS  Google Scholar 

  25. Bryan LE, Van Der Elzen HM. Effects of membrane-energy mutations and cations on streptomycin and gentamicin accumulation by bacteria: a model for entry of streptomycin and gentamicin in susceptible and resistant bacteria. Antimicrob Agents Chemother 1977; 12: 163–77

    Article  PubMed  CAS  Google Scholar 

  26. Karlowsky JA, Hoban DJ, Zelenitsky SA, et al. Altered denA and anr gene expression in aminoglycoside adaptive resistance in Pseudomonas aeruginosa. J Antimicrob Chemother 1997; 40: 371–6

    Article  PubMed  CAS  Google Scholar 

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Barclay, M.L., Begg, E.J. Aminoglycoside Adaptive Resistance. Drugs 61, 713–721 (2001). https://doi.org/10.2165/00003495-200161060-00001

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