Drug Exposure and Minimum Inhibitory Concentration in the Treatment of MAC Lung Disease

Summary

The incidence and prevalence of nontuberculous mycobacteria (NTM) infections have gradually increased over the years worldwide (1-3). In China, Mycobacterium avium complex (MAC) was the most prevalent NTM specie (4), while challenged by long treatment duration, frequent drug-induced adverse events, lack of treatment alternatives, poor treatment outcome and high recurrence rate (5, 6). In order to maximize the efficacy of the few available drugs and prevent the development of drug resistance, ensuring adequate plasma drug concentrations are of importance. Despite the role of pathogen susceptibility, determined by minimum inhibitory concentration (MIC), is non-negligible, the evidences regarding its association with treatment outcome are limited, especially for rifamycin and ethambutol. The difficulties in explaining the clinical values of MIC might partially be attributed to the lack of in vivo drug exposure data, which cannot be accurately predicted by the dose administered because of between-patient pharmacokinetic variability (7). Therapeutic drug monitoring (TDM) is a strategy to guide and personalize treatment by measuring plasma drug concentrations and pathogen susceptibility, which might have the potential to improve treatment response to MAC lung disease.

In this observational study, the hypothesis is that the drug exposure and/or MIC of antimycobacterial drugs are correlated to the treatment response of MAC lung disease, which is assessed from the perspective of treatment outcome, mycobacterial culture negative conversion, lung function, radiological presentation and self-reported quality of life. Consenting adult patients with culture-positive MAC lung disease will be recruited in study hospital. Respiratory samples (sputum and/or bronchoalveolar lavage fluid) will be collected regularly for mycobacterial culture on the basis of BACTEC MGIT 960 system and MIC will be determined using a commercial broth microdilution plate. Drug concentrations will be measured at 1 and/or 6 months after treatment initiation using liquid chromatography tandem mass spectrometry (LC-MS/MS). The final treatment outcome is recorded at the end of MAC treatment and defined according to an NTM-NET consensus statement (8).

Conditions

• Mycobacterium Avium Complex
• Mycobacterium Avium-Intracellulare Infection
• Gram-Positive Bacterial Infections
• Mycobacterium Infections

Interventions

OTHER

Drug exposure

Drug concentrations will be measured after one-month antimycobacterial treatment. Area under drug concentration-time curve (AUC) and maximum concentration (Cmax) will be calculated.

Sponsors & Collaborators

• Fudan University

  collaborator OTHER

• University of Sydney

  collaborator OTHER

• Karolinska Institutet

  collaborator OTHER

• Shanghai Municipal Center for Disease Control and Prevention

  collaborator OTHER

• Shanghai Pulmonary Hospital, Shanghai, China

  lead OTHER

Principal Investigators

• Wei Sha, MD, Prof · Shanghai Pulmonary Hospital, Shanghai, China

• Xubin Zheng, MPH, PhD · Shanghai Pulmonary Hospital, Shanghai, China

• Biao Xu, Prof · Fudan University

• Jan-Willem Alffenaar, PhamD, Prof · University of Sydney

• Judith Bruchfeld, Ass. Prof · Karolinska Institutet

• Yi Hu, Ass. Prof · Fudan University

• Lina Davies Forsman, MD, PhD · Karolinska Institutet

• Yangyi Zhang, MPH · Shanghai Municipal Center for Disease Control and Prevention

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2023-04-14

Primary Completion

2025-10-31

Completion

2026-10-31

Countries

• China

Study Locations