Editor's Note: Non-tuberculous mycobacteria (NTM) refers to all mycobacteria other than Mycobacterium tuberculosis and Mycobacterium leprae. NTM most commonly affect the lungs, causing NTM pulmonary disease (NTM-PD), which can even lead to disseminated disease in immunocompromised individuals. In recent years, with changes in the environment, updates in detection technology, and increased awareness among physicians, the incidence of NTM-PD has been steadily increasing, with Mycobacterium avium complex (MAC) pulmonary disease being the most common worldwide. At the recent Fourth National Conference of the Chinese Medical Association on Bacterial and Fungal Infections (BISC 2024), Professor Hongfei Duan from the Department of Tuberculosis, Beijing Chest Hospital, Capital Medical University, delivered a fascinating presentation titled "Advances in Diagnosis and Treatment of Mycobacterium avium Complex Pulmonary Disease," elucidating and analyzing the current status, challenges, and progress in the diagnosis and treatment of MAC pulmonary disease.01 Diagnosis and Treatment Status of Mycobacterium avium Complex Pulmonary Disease
MAC Bacteria
Previously, MAC was thought to mainly include M. avium and M. intracellulare, but currently, MAC comprises at least 12 species of bacteria. Some MAC species have low pathogenicity, while others cause infections in uncommon sites.
Clinical Classification
The typical imaging manifestation of NTM-PD is upper lobe cavitation or bronchiectasis with multiple segmental bronchiectasis. In NTM-PD diagnosed at Beijing Chest Hospital, 97.2% exhibit typical manifestations of NTM-PD.
Treatment Regimen
Treatment recommendations are based on guidelines such as the American Thoracic Society’s “2020 NTM Disease Treatment Guidelines” and the Chinese Medical Association’s “Diagnosis and Treatment Guidelines for NTM Disease (2020 Edition).” The treatment endpoint is sputum culture conversion for 12 months, with a cure rate of 60%-80%.
Regarding the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of macrolides in the treatment of MAC pulmonary disease, the concentration of clarithromycin in unaffected lung tissue is 30-40 times higher than in plasma and more than 100 times higher in inflammatory cells than in plasma. The concentration of clarithromycin decreases gradually as it enters peripheral and deep-seated caseous lesions, with concentrations in caseum higher than in plasma. Macrolides have anti-inflammatory properties, helping to control harmful inflammatory reactions during acute and chronic bacterial infections and inhibiting biofilm growth.
However, due to the heterogeneity of MAC growth, there are no drugs with bactericidal or bacteriostatic effects on MAC diseases. The core drug macrolides only have bacteriostatic effects.
Guidelines have been updated regarding the treatment regimen for MAC pulmonary disease, recommending azithromycin as an alternative to clarithromycin for several reasons: Firstly, azithromycin’s blood concentration is less influenced by rifampicin, aiding in maintaining stable therapeutic effects. Secondly, using azithromycin can avoid potential interactions between clarithromycin and drugs like rifampicin, reducing the occurrence of adverse reactions. Lastly, azithromycin’s fewer dosing times and granules provide a more convenient dosing regimen for patients. For patients with cavity or severe nodular bronchiectasis, amikacin is used in combination. Studies have shown that the cure rate of the three-drug regimen with macrolides + amikacin is significantly higher than that without amikacin.
02 Challenges in the Diagnosis and Treatment of Mycobacterium avium Complex Pulmonary Disease
Determining Whether Detected Bacteria are Pathogenic
Diagnostic methods for NTM diseases mainly include culture-based and non-culture-based methods. Although culture methods are classic, they are time-consuming, less efficient, and can lead to false-negative results. Additionally, paraffin sections cannot be cultured, making identification impossible. In contrast, non-culture methods are rapid and can identify paraffin sections, being effective even in samples with positive acid-fast staining but negative Xpert MTB/RIF. However, non-culture methods have false-positive issues and require calibration during use.
Different guidelines have varying opinions on the use of molecular biology methods. The 2016 guidelines from the American Cystic Fibrosis Foundation and the European Cystic Fibrosis Society do not recommend routinely using molecular biology methods for direct species identification of mycobacteria from clinical specimens. However, the Chinese Medical Association’s “Diagnosis and Treatment Guidelines for NTM Disease (2020 Edition)” believe that both culture and molecular biology methods can serve as bacteriological diagnostic criteria. Establishing a strict laboratory quality control system is crucial to ensure diagnostic accuracy. Laboratory results should be repeatedly validated and combined with comprehensive clinical diagnosis to reach accurate conclusions.
High-throughput sequencing technology can detect NTM in both NTM-PD patients and healthy individuals. A study covering 31 NTM-PD patients and 11 controls showed that each sputum sample could detect an average of 5.5 NTM species through high-throughput sequencing. Importantly, the bacteria with the highest abundance detected by high-throughput sequencing did not completely match the sputum culture results. Even in the control group of 11 healthy individuals, high-throughput sequencing detected NTM, including MAC, M. abscessus, M. simiae, and M. terrae, among other types.
When determining the pathogenic potential of NTM, the following points need to be considered:
1. Species identification results: Generally, Mycobacterium kansasii is highly pathogenic, followed by MAC and M. abscessus, while M. fortuitum and M. simiae have relatively low pathogenicity, and M. gordonae and M. terrae have even lower pathogenicity.
2. Imaging characteristics: Patients with typical imaging manifestations, such as upper lobe cavitation or multiple segmental bronchiectasis with bronchial wall thickening, are more likely to be infected with highly pathogenic NTM.
3. Specimen source: Fluids and biopsy specimens from sterile sites usually provide more accurate diagnostic information, with higher diagnostic value than bronchoalveolar lavage fluid, while the diagnostic value of sputum samples is relatively low.
Principles of Antimicrobial Susceptibility Testing for NTM Clinical Isolates
1. To avoid resource waste and misleading treatment, susceptibility testing should only be performed on highly pathogenic strains. For clinically isolated NTM strains confirmed to be pathogenic, susceptibility testing should be considered, while it is unnecessary for strains with low pathogenic potential.
2. Susceptibility testing should focus on drugs that significantly affect the prognosis of NTM diseases. For example, in the case of MAC, susceptibility testing of macrolides is recommended rather than rifampicin and ethambutol.
3. When performing susceptibility testing, standardized methods and resistance breakpoints recommended by the Clinical and Laboratory Standards Institute should be followed. Liquid culture media are recommended, and the resistance breakpoints for clarithromycin against MAC are 32mg/L and 8mg/L for rapidly growing mycobacteria.
4. Susceptibility testing should be actively performed for NTM with potential resistance. Particularly for refractory MAC pulmonary disease, susceptibility testing of macrolides should be prioritized.
Rational Evaluation Methods for Treatment Efficacy
The main methods for evaluating the efficacy of NTM disease treatment include symptom relief (PRO), microbiological conversion, and radiological improvement. Among them, sputum culture conversion is the gold standard for evaluating efficacy, directly correlating with disease improvement and closely associated with reduced mortality rates. However, achieving microbiological conversion may be challenging for some refractory MAC pulmonary disease and M. abscessus pulmonary disease patients. Therefore, other indicators need to be considered when evaluating efficacy.
In addition to sputum culture conversion, the speed of sputum culture conversion and the six-minute walk test are also used as evaluation criteria for MAC pulmonary disease efficacy. Studies have shown that patients treated with amikacin liposomes achieve faster sputum culture conversion rates than those in other treatment groups, and the sputum culture conversion group performs significantly better in the six-minute walk test than the non-conversion group. Radiological improvement is widely used in clinical practice, but due to a lack of quantitative standards, evaluation results may be subjective.
03 Progress in the Diagnosis and Treatment of Mycobacterium avium Complex Pulmonary Disease
Timing of Treatment
For confirmed NTM pulmonary disease, immediate initiation of treatment is recommended, especially for patients with positive acid-fast staining of sputum smears and lung cavitation.
Features of spontaneous sputum culture conversion in MAC pulmonary disease include young age, normal body mass index, and negative acid-fast staining of sputum smears; features of progression in MAC pulmonary disease include fibrocavitary type, extensive pulmonary lesions, and positive acid-fast staining of sputum smears.
Research on New Drugs
1. Treatment of refractory MAC pulmonary disease with amikacin liposomes. The cure rate of the standard treatment regimen for MAC pulmonary disease is approximately 65%. However, due to various reasons, some patients’ conditions are difficult to control effectively. These refractory factors mainly include macrolide resistance (about 21.8%), reinfection (about 73%), and drug intolerance. Studies have shown that the sputum culture conversion rate is significantly higher in patients treated with amikacin liposomes than in the control group.
2. Exploration of clofazimine in the treatment of MAC pulmonary disease. A study conducted at Beijing Chest Hospital included 50 patients with MAC pulmonary disease treated with clofazimine, of which 25 had previously received anti-tuberculosis treatment, and another 25 were unsuitable for using amikacin. The study found that the MIC50 and MIC90 values of clofazimine in patients who had received anti-tuberculosis treatment were significantly higher than those in patients who had not received anti-tuberculosis treatment, suggesting that previous anti-tuberculosis treatment may have an impact on the efficacy of clofazimine. Further analysis showed that a clofazimine MIC value of less than 0.25mg/L was a key factor affecting the sputum culture conversion rate (P=0.004), and when the clofazimine MIC was <0.25mg/L, the sputum culture conversion rate of patients significantly increased (P=0.006).
3. Application of bacteriophage therapy. In a study, 20 patients with refractory mycobacterial disease (17 with M. abscessus, 1 with M. simiae, 1 with M. avium, and 1 with BCG) received bacteriophage therapy, all without adverse reactions. Among them, 11 patients showed good efficacy. In 8 patients receiving intravenous bacteriophage injection, neutralizing antibodies were detected in serum, and among them, 4 had poor efficacy. Additionally, 11 patients receiving only single bacteriophage therapy did not develop bacteriophage resistance.
Understanding Recurrent Infections
Accurately distinguishing reinfection from treatment failure is crucial in evaluating the treatment efficacy of MAC pulmonary disease. A study showed that among 72 patients treated for more than 12 months but with positive sputum cultures, only 22% exhibited macrolide resistance. Mycobacterial genotyping of 49 patients showed that 73% of patients were reinfected with new MAC strains, while 27% had persistent infection with the original MAC strain.
Another study pointed out that the imaging types of reinfection with NTM are not limited to nodular bronchiectasis but also include upper lobe cavitation. In patients with treatment failure of M. abscessus pulmonary disease, up to 92% were due to reinfection.
Moreover, nodular bronchiectasis is an independent risk factor for recurrence.
04 Conclusion
When diagnosing NTM disease, the discovery of NTM in clinical specimens is not sufficient for diagnosis. Factors such as bacterial type, specimen source, and imaging characteristics need to be considered comprehensively to accurately determine their relevance to the disease. In terms of treatment, NTM disease treatment should be initiated cautiously and promptly, and treatment efficacy should be scientifically evaluated. Additionally, close attention to the latest research findings and optimization of treatment regimens based on these findings are necessary. Furthermore, exploring the mechanisms that affect NTM disease efficacy is crucial for a comprehensive understanding of the disease and the development of more precise treatment strategies.
