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

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

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).

Study Overview

• Status: Recruiting
• Conditions: Gram-Positive Bacterial Infections; Mycobacterium Infections; Mycobacterium Avium-Intracellulare Infection; Mycobacterium Avium Complex
• Intervention / Treatment: Other: Drug exposure

Detailed Description

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.

• Study Type: Observational
• Enrollment (Estimated): 100

Contacts and Locations

• Study Contact: Name: Wei Sha, MD, Prof; Phone Number: 2017 86 21 65115006; Email: shfksw@126.com
• Study Contact Backup: Name: Xubin Zheng, MPH, PhD; Phone Number: 3181 86 21 65115006; Email: xbzheng@tongji.edu.cn

Study Locations

• China
  • Shanghai, China, 200433
    • Recruiting
    • Shanghai Pulmonary Hospital
    • Contact: Xubin Zheng, MPH, PhD; Phone Number: 3181 86 21 65115006; Email: xbzheng@tongji.edu.cn
    • Sub-Investigator: Yidian Liu, MD, PhD
    • Sub-Investigator: Li Wang, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

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.

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Patients with MAC lung disease	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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Shanghai Pulmonary Hospital, Shanghai, China
• Collaborators: Karolinska Institutet; Fudan University; University of Sydney; Shanghai Municipal Center for Disease Control and Prevention
• Investigators: Principal Investigator: Wei Sha, MD, Prof, Shanghai Pulmonary Hospital, Shanghai, China; Study Director: Xubin Zheng, MPH, PhD, Shanghai Pulmonary Hospital, Shanghai, China; Study Chair: Biao Xu, Prof, Fudan University; Study Chair: Jan-Willem Alffenaar, PhamD, Prof, University of Sydney; Study Chair: Judith Bruchfeld, Ass. Prof, Karolinska Institutet; Study Chair: Yi Hu, Ass. Prof, Fudan University; Study Chair: Lina Davies Forsman, MD, PhD, Karolinska Institutet; Study Chair: Yangyi Zhang, MPH, Shanghai Municipal Center for Disease Control and Prevention

Publications and helpful links

General Publications

• Winthrop KL, Marras TK, Adjemian J, Zhang H, Wang P, Zhang Q. Incidence and Prevalence of Nontuberculous Mycobacterial Lung Disease in a Large U.S. Managed Care Health Plan, 2008-2015. Ann Am Thorac Soc. 2020 Feb;17(2):178-185. doi: 10.1513/AnnalsATS.201804-236OC.
• Lee H, Myung W, Koh WJ, Moon SM, Jhun BW. Epidemiology of Nontuberculous Mycobacterial Infection, South Korea, 2007-2016. Emerg Infect Dis. 2019 Mar;25(3):569-572. doi: 10.3201/eid2503.181597.
• Ringshausen FC, Wagner D, de Roux A, Diel R, Hohmann D, Hickstein L, Welte T, Rademacher J. Prevalence of Nontuberculous Mycobacterial Pulmonary Disease, Germany, 2009-2014. Emerg Infect Dis. 2016 Jun;22(6):1102-5. doi: 10.3201/eid2206.151642.
• Tan Y, Deng Y, Yan X, Liu F, Tan Y, Wang Q, Bao X, Pan J, Luo X, Yu Y, Cui X, Liao G, Ke C, Xu P, Li X, Zhang C, Yao X, Xu Y, Li T, Su B, Chen Z, Ma R, Jiang Y, Ma X, Bi D, Ma J, Yang H, Li X, Tang L, Yu Y, Wang Y, Song H, Liu H, Wu M, Yang Y, Xue Z, Li L, Li Q, Pang Y. Nontuberculous mycobacterial pulmonary disease and associated risk factors in China: A prospective surveillance study. J Infect. 2021 Jul;83(1):46-53. doi: 10.1016/j.jinf.2021.05.019. Epub 2021 May 25.
• Kwak N, Park J, Kim E, Lee CH, Han SK, Yim JJ. Treatment Outcomes of Mycobacterium avium Complex Lung Disease: A Systematic Review and Meta-analysis. Clin Infect Dis. 2017 Oct 1;65(7):1077-1084. doi: 10.1093/cid/cix517.
• Diel R, Nienhaus A, Ringshausen FC, Richter E, Welte T, Rabe KF, Loddenkemper R. Microbiologic Outcome of Interventions Against Mycobacterium avium Complex Pulmonary Disease: A Systematic Review. Chest. 2018 Apr;153(4):888-921. doi: 10.1016/j.chest.2018.01.024. Epub 2018 Feb 2.
• Magis-Escurra C, Alffenaar JW, Hoefnagels I, Dekhuijzen PN, Boeree MJ, van Ingen J, Aarnoutse RE. Pharmacokinetic studies in patients with nontuberculous mycobacterial lung infections. Int J Antimicrob Agents. 2013 Sep;42(3):256-61. doi: 10.1016/j.ijantimicag.2013.05.007. Epub 2013 Jul 7.
• van Ingen J, Aksamit T, Andrejak C, Bottger EC, Cambau E, Daley CL, Griffith DE, Guglielmetti L, Holland SM, Huitt GA, Koh WJ, Lange C, Leitman P, Marras TK, Morimoto K, Olivier KN, Santin M, Stout JE, Thomson R, Tortoli E, Wallace RJ Jr, Winthrop KL, Wagner D; for NTM-NET. Treatment outcome definitions in nontuberculous mycobacterial pulmonary disease: an NTM-NET consensus statement. Eur Respir J. 2018 Mar 22;51(3):1800170. doi: 10.1183/13993003.00170-2018. Print 2018 Mar. No abstract available.
• Daley CL, Iaccarino JM, Lange C, Cambau E, Wallace RJ Jr, Andrejak C, Bottger EC, Brozek J, Griffith DE, Guglielmetti L, Huitt GA, Knight SL, Leitman P, Marras TK, Olivier KN, Santin M, Stout JE, Tortoli E, van Ingen J, Wagner D, Winthrop KL. Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDSA clinical practice guideline. Eur Respir J. 2020 Jul 7;56(1):2000535. doi: 10.1183/13993003.00535-2020. Print 2020 Jul.
• Alffenaar JW, Martson AG, Heysell SK, Cho JG, Patanwala A, Burch G, Kim HY, Sturkenboom MGG, Byrne A, Marriott D, Sandaradura I, Tiberi S, Sintchencko V, Srivastava S, Peloquin CA. Therapeutic Drug Monitoring in Non-Tuberculosis Mycobacteria Infections. Clin Pharmacokinet. 2021 Jun;60(6):711-725. doi: 10.1007/s40262-021-01000-6. Epub 2021 Mar 10.

Study record dates

Study Major Dates

• Study Start (Actual): April 14, 2023
• Primary Completion (Estimated): October 1, 2025
• Study Completion (Estimated): October 1, 2026

Study Registration Dates

• First Submitted: March 24, 2023
• First Submitted That Met QC Criteria: April 10, 2023
• First Posted (Actual): April 24, 2023

Study Record Updates

• Last Update Posted (Actual): January 22, 2024
• Last Update Submitted That Met QC Criteria: January 19, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Treatment; Pharmacokinetics; Pharmacodynamics; Minimum Inhibitory Concentration; Drug Concentration
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Disease Attributes; Bacterial Infections and Mycoses; Actinomycetales Infections; Mycobacterium Infections, Nontuberculous; Lung Diseases; Infections; Communicable Diseases; Mycobacterium Infections; Bacterial Infections; Mycobacterium avium-intracellulare Infection; Gram-Positive Bacterial Infections
• Other Study ID Numbers: K22-149Z

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO