Vignaud Etienne, Goutelle Sylvain, Genestet Charlotte, Guitton Jérôme, Cohen Sabine, Bourg Chloé, Durand Aurore, Lebouteiller Laura, Bernard Albin, Richet Caroline, Dumitrescu Oana, Hodille Elisabeth
Laboratoire des Mycobactéries, Institut des Agents Infectieux, Laboratoire de Biologie Médicale Multi-Site, Hôpital de la Croix Rousse, Hospices Civils de Lyon, Lyon, France.
Service de Pharmacie, Groupement Hospitalier Nord, Hospices Civils de Lyon, Lyon, France.
Ann Clin Microbiol Antimicrob. 2025 Jan 30;24(1):10. doi: 10.1186/s12941-025-00776-w.
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.
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.
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.
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.
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.
脓肿分枝杆菌（MABS）可引起难以治疗的肺部和肺外感染。推荐使用阿米卡星、头孢西丁和大环内酯类药物联合治疗，但这种联合疗法的抗菌活性和临床疗效尚不确定。大环内酯类药物诱导性耐药（macrolides-iR）与肺部感染的临床反应不佳有关，而关于肺外感染的数据较少。
本文旨在评估在中空纤维感染模型中，阿米卡星、头孢西丁和克拉霉素联合用药对macrolides-iR MABS的治疗效果。
将脓肿分枝杆菌亚种脓肿型菌株ATCC 19977接种到中空纤维系统中，并用抗生素联合治疗10天。模拟血液和肺中游离（即未结合）药物的药代动力学特征，评估两种大环内酯浓度水平。
采用血液浓度时，联合用药未能阻止细菌生长。采用肺浓度时，联合用药在第2天至第10天对细菌生长有有限但显著的影响。此外，增加克拉霉素浓度可稳定阿米卡星的耐受水平：使用血液浓度时，耐阿米卡星菌株的阿米卡星最低抑菌浓度随时间增加，而使用肺浓度时则保持稳定。
我们的研究结果证实了阿米卡星、头孢西丁和克拉霉素联合用药对macrolide-iR MABS感染的活性较低，并提示克拉霉素浓度对治疗反应有影响。血液中克拉霉素浓度较低可能会妨碍肺外MABS感染的治疗效果。因此，不应将其视为所选抗生素联合用药中的活性分子，而最近有推荐将其用于肺部感染治疗。
