Survey on therapeutic drug monitoring practices for nontuberculous mycobacterial infections: an NTMnet/ESGMYC collaborative study

Extract

The treatment of nontuberculous mycobacterial (NTM) disease is lengthy and requires multiple drugs, often associated with adverse effects [1]. Treatment failure and recurrence are also common [2]. Drug over- and underexposure may contribute to toxicity and treatment failure [3–5]. Still, information on the use of therapeutic drug monitoring (TDM) – the individualisation of drug dosing based on drug concentration measurements – to optimise NTM disease management is very limited.

Shareable abstract

TDM use in NTM management varies globally, with over half using it despite significant barriers. Safety seemed the main reason. Standardised protocols and clear guidelines are needed for effective and consistent TDM implementation. https://bit.ly/3TFYN2j

To the Editor:

The treatment of nontuberculous mycobacterial (NTM) disease is lengthy and requires multiple drugs, often associated with adverse effects [1]. Treatment failure and recurrence are also common [2]. Drug over- and underexposure may contribute to toxicity and treatment failure [3–5]. Still, information on the use of therapeutic drug monitoring (TDM) – the individualisation of drug dosing based on drug concentration measurements – to optimise NTM disease management is very limited. Only a few studies have examined its clinical implications [3–6]. Given that European Respiratory Society and European Society of Clinical Microbiology and Infectious Diseases guidelines suggest considering TDM for NTM pulmonary disease, investigating its clinical application, utility and barriers is highly relevant. We aimed to describe the global use of TDM in NTM disease management and to identify barriers to its broader implementation.

We conducted an international online survey targeting NTM experts. A comprehensive questionnaire covering respondent characteristics, TDM use and barriers was developed by the co-authors, including two pharmacist experts, and reviewed by NTMnet and ESGMYC (ESCMID Study Group for Mycobacterial Infections). The codebook and supplementary material are available upon request. The survey was distributed through NTMnet, ESGMYC, NTM Network UK, and the US Bronchiectasis and NTM Research Registry Program. REDCap was utilised for data collection. Descriptive statistics were used to summarise the data using R v. 4.2.3. Survey respondents voluntarily and anonymously participated, and ethical approval was not required.

We received 160 responses, of which six were unfilled and 23 incomplete, leaving 131 for analysis. Respondents represented 35 countries, with the majority from the UK (n=34), the US (n=18), the Netherlands (n=9), Italy (n=8), and Germany (n=5). Respondents were clinicians (82%), researchers (19%), pharmacists (7.6%), microbiologists (5.3%), other professionals (4.6%), public health staff (2.3%), or a combination. Most (65%) had >10 years of experience and worked in academic/university hospitals (68%).

Overall, 58% (n=76) reported using TDM, with considerable variability across and within countries (figure 1a). Among those who used TDM, 26% (n=20) did so routinely for all patients. The primary indications for TDM included treatment failure (70%), gastrointestinal disease/malabsorption (57%), drug–drug interactions (55%), and severe adverse effects (46%). Among respondents who did not use TDM (n=55), the most frequently reported reasons were laboratory unavailability (36%), absence of guideline recommendations (31%), and a lack of evidence regarding its impact on outcomes (31%). Main barriers reported by both users and non-users included unclear clinical implications (37%), lack of guidelines (37%), impracticality in routine care (35%), and high resource demands (35%). TDM use varied significantly by drug (figure 1b). Amikacin was the most frequently monitored drug (92%, n=70/76), followed by rifampicin (61%), ethambutol (49%) and linezolid (46%). For macrolides, 38% used TDM for azithromycin and 17% for clarithromycin. For amikacin, both the peak concentration (C_max, related to efficacy, 61%) and the trough concentration (C_min, related to adverse effects, 83%) were frequently sampled. TDM strategies for other drugs involved assessing C_max, C_min and total exposure (area under the curve) at varying frequencies, though many respondents indicated uncertainty regarding their sampling methods. Laboratory analyses were predominantly performed locally (42%) or nationally (34%). Only 25% (n=19) of respondents were aware of the laboratory methods used, with liquid chromatography–mass spectrometry being the most common technique (74%), followed by high-performance liquid chromatography with ultraviolet/fluorescence detection (63%). TDM results were usually available within one week (53%), although some took one to two weeks (29%) or more than two weeks (12%). Dose adjustments (95%) and confirmation (89%) were the most common outcomes of TDM, while changes in drug (38%) or administration route (26%) occurred less frequently.

FIGURE 1.

a) World map showing survey responses on the use of therapeutic drug monitoring (TDM) for nontuberculous mycobacterial disease management by country. Countries are shaded based on TDM use (green), use by some (yellow), no use (red) or grey (no respondents). Numbers indicate the fraction and percentage of respondents using TDM in each country. An inset highlights detailed responses in Europe. b) Bar charts showing which pharmacokinetic parameters survey respondents monitor for different drugs used to treat nontuberculous mycobacterial disease. Each chart represents one drug, with bars showing the percentage of respondents monitoring area under the curve (green), C_max (red), C_min (yellow), or indicating they do not know (grey).

Currently, there is limited information to guide clinical practice on TDM in NTM disease. Despite many respondents' claims of lacking recommendations, the current international guideline for NTM pulmonary disease does suggest considering TDM in selected cases, such as the presence of malabsorption, suspected drug underdosing, or drug–drug interactions, though practical recommendations remain lacking [1]. Additionally, TDM is mentioned as potentially beneficial in cases of delayed sputum culture conversion or treatment failure, particularly when nonadherence and drug resistance (i.e., to macrolides and amikacin) have been ruled out. It is also suggested for the safety monitoring of aminoglycoside treatment or those with comorbidities at higher risk of underdosing or toxicity [1]. Interestingly, while many respondents emphasise TDM for treatment failure, our survey indicates that it is primarily used for safety monitoring. The most frequently measured drug concentrations are those associated with the highest risk of adverse effects, particularly amikacin, but also rifampicin, ethambutol and linezolid, whereas concentrations of macrolides are less frequently ordered, despite the relevance of macrolide exposures for NTM treatment response [5]. Aminoglycoside TDM may already be integrated into many hospital and pharmacy protocols and is facilitated by commercially available and easy-to-operate immuno-assays, making clinicians more familiar with this option than other drugs.

Although randomised controlled trials on TDM's impact on clinical outcomes, such as culture conversion or adverse effects, are lacking, it is reasonable to assume that dose optimisation based on TDM could lead to improvement [7, 8], and the majority of respondents seem to agree with this. Jeong et al. [5] observed that a higher C_max of azithromycin was independently associated with more favourable microbiological responses in patients with Mycobacterium avium complex lung disease, but only with daily dosing (250 mg), and not with thrice-weekly dosing (500 mg). Similarly, Zweijpfenning et al. [6] showed that patients with 6-month culture conversion had a higher clofazimine C_max. In contrast, Koh et al. [4] found no significant difference in peak plasma clarithromycin concentration/minimal inhibitory concentration ratios between patients with unfavourable and favourable treatment outcomes, yet the entire cohort had very low clarithromycin exposures, and the methodology of this analysis was questioned. More research on exposure–response relationships in NTM treatment is warranted.

Many survey respondents reported that TDM led to changes in drug dosing, supporting previous findings of underdosing being common in NTM disease [3, 4, 9]. Future research should focus on evaluating the role of TDM in improving culture conversion rates, reducing adverse effects, and ultimately guiding more effective treatment strategies [10]. Without robust evidence, clinicians may continue to rely on TDM strategies from tuberculosis management [11], but tailored guidelines specific to NTM disease are crucial for advancing clinical practice.

A limitation of our study is the potential overrepresentation of certain countries and institutions, potentially biasing TDM use compared to the broader community. Moreover, our sample may not fully represent the global target population for potential TDM use, particularly in resource-limited settings. However, we did include representatives from countries with the highest reported prevalence of NTM disease. Finally, another limitation is that we did not include questions specifically addressing difficulties with interpreting TDM results or adapting antibiotic dosing, which may be important factors influencing clinical use. Prospective studies are warranted to investigate the impact of TDM on patient outcomes and dosing decisions, as these questions cannot be fully addressed through a survey-based approach.

Our survey highlights the current global landscape of TDM use in NTM disease management, revealing significant variability in its application across different countries and drugs. Over half of the respondents use TDM, predominantly for safety monitoring. Barriers such as unclear clinical implications, insufficient evidence regarding its impacts and high resource demands remain key challenges. The study underscores the need for more pharmacokinetic–pharmacodynamic research, standardised protocols, and comprehensive clinical guidelines to guide TDM implementation in NTM management.