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).
Culture-positive MAC lung disease
MAC treatment at the Shanghai Pulmonary Hospital
A regimen composed of at least the core drugs, i.e., macrolides, rifamycin and ethambutol, in doses not lower than recommended according to the ATS/ERS/ESCMID/IDSA and Chinese national guidelines
Written informed consent
Pregnancy
Confirmed mixed infection with mycobacterial species, including M.tuberculosis and other NTM species
Ongoing with any antimycobacterial treatment for more than one month, including tuberculosis and NTM
Patients admitted to the intensive care unit
All adult patients diagnosed with and treated for MAC lung disease in study hospital in Shanghai, China will be screened for eligibility. Patients will be informed and asked to participate in the study both orally and in writing.
Cohort
Prospective
Drug exposure
Other interventionDrug concentrations will be measured after one-month antimycobacterial treatment. Area under drug concentration-time curve (AUC) and maximum concentration (Cmax) will be calculated.
Peak plasma concentration (Cmax) for key antimycobacterial drugs, separate and in relation to minimum inhibitory concentration
Descriptive data of the distribution of Cmax for key antimycobacterial drugs in patients with MAC lung disease, with regard to existing recommended levels. Their associations with treatment response will be investigated.
Area under the plasma concentration versus time curve (AUC) for key antimycobacterial drugs, separate and in relation to minimum inhibitory concentration
Descriptive data of the distribution of AUC for key antimycobacterial drugs in patients with MAC lung disease, with regard to existing recommended levels. Their associations with treatment response will be investigated.
Proportion of patients with cure of MAC lung disease
The proportion of patients with cure of MAC lung disease at the end of treatment. The definition of treatment outcome will refer to an NTM-NET consensus statement, on the basis of mycobacterial culture as well as patient-reported and/or objective improvement of symptoms.
Six-month culture conversion
The proportion of patients with culture negative conversion after 6 months of MAC treatment.
Time to culture conversion
Time (in months) from start of treatment until the first out of three consecutive negative cultures, collected at least 30 days apart.
Proportion of patients with significant changes in drug resistance profile
The proportion of patients with significant changes in the drug resistance profile, phenotypic (MIC) and genotypic (whole genome sequencing) of the antimycobacterial drugs used, during MAC treatment.
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Shanghai Pulmonary Hospital, Shanghai, China
Lead sponsor
Fudan University
Collaborator
University of Sydney
Collaborator
Karolinska Institutet
Collaborator
Shanghai Municipal Center for Disease Control and Prevention
Collaborator
