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Background <p><i>Mycobacterium abscessus</i> (MABS) causes difficult-to-treat pulmonary and extra-pulmonary infections. A combination therapy comprising amikacin, cefoxitin, and a macrolide agent is recommended, but its antimicrobial activity and clinical efficacy is uncertain. Inducible resistance to macrolides (macrolides-iR) has been associated with poor clinical response in pulmonary infections, whilst for extra-pulmonary infections data are scarce.</p> Objectives <p>Herein, the aim was to evaluate the effect of the amikacin, cefoxitin, and clarithromycin combination against macrolides-iR MABS in a hollow-fiber infection model.</p> Methods <p>The hollow-fiber system was inoculated with <i>M. abscessus</i> subsp. <i>abscessus</i> type strain ATCC 19977 and treated during 10&#xa0;days with the antibiotics combination. Two level of macrolide concentrations were evaluated mimicking the pharmacokinetics profiles of free (i.e. unbound) drug in blood and lung.</p> Results <p>Using blood concentrations, the combination failed to prevent bacterial growth. Using lung concentrations, the combination had a limited but significant effect on bacterial growth from day 2 to day 10. Moreover, increasing clarithromycin concentrations stabilized the amikacin-tolerance level: amikacin minimal inhibitory concentration of amikacin-tolerant strains increased over time using blood concentrations while it remained stable using lung concentrations.</p> Conclusions <p>Our finding confirms the low activity of the amikacin, cefoxitin, and clarithromycin combination against macrolide-iR MABS infection, and suggest the influence of clarithromycin concentrations on response. The low concentration of clarithromycin in blood may hamper efficacy for the treatment of extra-pulmonary MABS infection. Consequently, it should not be considered as an active molecule in the chosen antibiotic combination, as recently recommended for pulmonary infections.</p>

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Poor efficacy of the combination of clarithromycin, amikacin, and cefoxitin against Mycobacterium abscessus in the hollow fiber infection model

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月30日

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  • Etienne Vignaud,
  • Sylvain Goutelle,
  • Charlotte Genestet,
  • Jérôme Guitton,
  • Sabine Cohen,
  • Chloé Bourg,
  • Aurore Durand,
  • Laura Lebouteiller,
  • Albin Bernard,
  • Caroline Richet,
  • Oana Dumitrescu,
  • Elisabeth Hodille

摘要

Background

Mycobacterium abscessus (MABS) causes difficult-to-treat pulmonary and extra-pulmonary infections. A combination therapy comprising amikacin, cefoxitin, and a macrolide agent is recommended, but its antimicrobial activity and clinical efficacy is uncertain. Inducible resistance to macrolides (macrolides-iR) has been associated with poor clinical response in pulmonary infections, whilst for extra-pulmonary infections data are scarce.

Objectives

Herein, the aim was to evaluate the effect of the amikacin, cefoxitin, and clarithromycin combination against macrolides-iR MABS in a hollow-fiber infection model.

Methods

The hollow-fiber system was inoculated with M. abscessus subsp. abscessus type strain ATCC 19977 and treated during 10 days with the antibiotics combination. Two level of macrolide concentrations were evaluated mimicking the pharmacokinetics profiles of free (i.e. unbound) drug in blood and lung.

Results

Using blood concentrations, the combination failed to prevent bacterial growth. Using lung concentrations, the combination had a limited but significant effect on bacterial growth from day 2 to day 10. Moreover, increasing clarithromycin concentrations stabilized the amikacin-tolerance level: amikacin minimal inhibitory concentration of amikacin-tolerant strains increased over time using blood concentrations while it remained stable using lung concentrations.

Conclusions

Our finding confirms the low activity of the amikacin, cefoxitin, and clarithromycin combination against macrolide-iR MABS infection, and suggest the influence of clarithromycin concentrations on response. The low concentration of clarithromycin in blood may hamper efficacy for the treatment of extra-pulmonary MABS infection. Consequently, it should not be considered as an active molecule in the chosen antibiotic combination, as recently recommended for pulmonary infections.