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

Study Overview
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Brief Summary
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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).

Detailed Description
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This is an observational cohort study conducted to enrol consenting adult patients with culture-positive MAC lung disease in study hospital (n=100). The diagnosis and treatment of MAC lung disease will adhere to the ATS/ERS/ESCMID/IDSA and Chinese national guidelines (9, 10). Patients treated with a regimen composed of macrolides, rifamycin and ethambutol at minimum are screened for eligibility. Detailed demographic, behaviour, clinical and laboratory information will be recorded at baseline. Respiratory samples (sputum and/or bronchoalveolar lavage fluid) will be collected at baseline and once every 3 months until treatment completion for mycobacterial culture using BACTEC MGIT 960. Time to mycobacterial culture positivity (TTP) will be recorded to estimate the bacterial load as an alternative for colony forming units count. MIC determination will be performed for baseline, six-month and/or the last available positive culture during treatment with the Sensititre™ SLOMYCO2 Susceptibility Testing Plate, to assess the development of acquired drug resistance. Drug concentrations will be measured for all study patients at one month after treatment initiation. Rich blood sampling (0, 1, 2, 4, 6 and 8 hours after drug intake) will be implemented for the first 30 patients aged < 65 years to enable the development of population pharmacokinetic models. A limited sampling strategy (2 and 6 hours after drug intake) will be applied for the rest patients to increase the feasibility of study. Additional blood sampling will be given for patients with poor treatment response at six months with limited sampling strategy. The developed pharmacokinetic models will be used to accurately calculate the area under the plasma concentration versus time curve (AUC) and peak plasma concentration (Cmax), as the main exposure variables. To comprehensively assess the response to MAC treatment, mycobacterial culture, lung function test, computerized tomography (CT) scan and questionnaires for well-being will be taken regularly in this study. The final treatment outcome is recorded at the end of MAC treatment and defined according to an NTM-NET consensus statement (8). Post-treatment visits are given at 6 and 12 months after treatment completion to assess the recurrence of MAC lung disease. Together with bacteria MIC and clinical data, the Cmax/MIC and AUC/MIC for antimycobacterial drugs will be explored to deepen our understandings on the correlation of pharmacokinetic and/or pharmacodynamic indices with treatment response, which may guide development of new dosing strategies.

Official Title
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Drug Exposure and Minimum Inhibitory Concentration in the Treatment of Mycobacterium Avium Complex Lung Disease: a Prospective Observational Cohort Study

Conditions
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Mycobacterium Avium Complex, Mycobacterium Avium-Intracellulare Infection, Gram-Positive Bacterial Infections, Mycobacterium Infections

Intervention / Treatment
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* Other: Drug exposure


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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 Off-label use for any study drugs, such as inhalation of amikacin

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients with MAC lung disease<br> | Other: Drug exposure<br>* Drug concentrations will be measured after one-month antimycobacterial treatment. Area under drug concentration-time curve (AUC) and maximum concentration (Cmax) will be calculated.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | one-month of treatment | 
| 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. | one-month of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 12-18 months | 
| Six-month culture conversion | The proportion of patients with culture negative conversion after 6 months of MAC treatment. | 6 months | 
| 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. | 12-18 months | 
| 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. | 12-18 months | 
| Resolution of pulmonary lesions or cavitation | Resolution or deterioration of pulmonary lesions or cavitation during MAC treatment by CT scan. | 12-18 months | 
| Proportion of patients with improved forced expiratory volume in 1 second (FEV1) | Decrease or increase of FEV1 during MAC treatment by lung function test. | 12-18 months | 
| Proportion of patients with improved forced vital capacity (FVC) | Decrease or increase of FVC during MAC treatment by lung function test. | 12-18 months | 
| Proportion of patients with improved quality of life | Improvement or deterioration of quality of life during MAC treatment by the St. George's Respiratory Questionnaire (SGRQ). The SGRQ score ranges from 0 to 100, with higher scores indicating more limitations. | 12-18 months | 
| Proportion of patients with grade 3 or 4 adverse events | The proportion of patients with grade 3 or 4 adverse events during MAC treatment, according to the Division of Acquired Immunodeficiency Syndrome (DAIDS) guidelines. | 12-18 months | 
| Number of patients with recurrence of MAC lung disease | The number of patients with recurrence of MAC lung disease within one year post treatment completion. | 24-30 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Treatment, Minimum Inhibitory Concentration, Drug Concentration, Pharmacokinetics, Pharmacodynamics