Treatment of NTM (non-tuberculous mycobacterial infection) disease
Most NTM are resistant to commonly used anti-mycobacterial drugs. Considering that the clinical treatment effect is mostly inexact, as well as the cost required for treatment and the adverse effects caused, clinicians should make a comprehensive judgment when deciding whether to treat or not. For patients with mild symptoms, limited lesions on chest imaging, insignificant changes after dynamic follow-up, and drug sensitivity test results of extensive and high resistance, it is difficult to achieve the desired efficacy with current drugs alone, or poorly tolerated patients with advanced NTM lung disease may not be given anti-mycobacterial therapy.
1. Since the resistance pattern of NTM can vary depending on the strain, it is still important to perform drug sensitivity testing before treatment.
2.Although it is difficult to determine the correlation between drug sensitivity test results and clinical outcomes, the treatment plan for NTM disease should still be formulated by selecting a combination of 5 to 6 drugs based on drug sensitivity test results and medication history as much as possible, with an intensive period of 6 to 12 months, a consolidation period of 12 to 18 months, and continued treatment for more than 12 months after negative NTM culture results.
3. The type of medication and duration of treatment may vary for different NTM diseases.
4., Experimental treatment is recommended for patients with suspected NTM lung disease.
5. Surgical treatment should be used with caution in patients with NTM lung disease.
(II) Therapeutic drugs
1. New macrolides: Clarithromycin and azithromycin, among the new macrolides, are considered to be the most important new drugs for the treatment of NTM disease, especially MAC (Mycobacterium avium complex) disease, in the past 20 years. The results of in vitro studies have shown that the new macrolides have strong antibacterial effects against NTM, especially MAC, Mycobacterium avium, Mycobacterium tortuis and Mycobacterium abscessus. The MICs of clarithromycin against MAC ranged from 0.25 to 4 mg/L, 2 mg/L and 0.125 mg/L against Mycobacterium avium and Mycobacterium tortuis, respectively, and 0.5 to 1.0 mg/L and 0.5 mg/L against Mycobacterium kansasii and Mycobacterium toadicum, respectively.Although the gallery concentrations of clarithromycin were low (1 to 4 mg/L), its macrophages and tissues, its concentration was higher.
2, rifamycin class drugs: rifampicin is a commonly used drug in the treatment of NTM disease and has certain efficacy; rifabutin is the most representative among the new rifamycin class drugs and has certain antibacterial effects on MAC, Mycobacterium kansasii, Mycobacterium avium, Mycobacterium tortuis and Mycobacterium abscessus in NTM, and its biggest advantage is that it has a weak induction effect on hepatic cytochrome P450-3A system In the treatment of patients with HIV-associated tuberculosis, antiretroviral therapy is needed at the same time as anti-tuberculosis treatment, and rifabutin has greater superiority than rifampin at this time.
3, ethambutol: Ethambutol is the most commonly used basic drug for the treatment of NTM disease. Ethambutol can inhibit the synthesis of Mycobacterium RNA and destroy the cell wall of Mycobacterium, so that it has some antibacterial activity against MTB and some NTM (such as MAC, Mycobacterium Kansas, Mycobacterium scrofula and Mycobacterium sea). There is no cross-resistance between ethambutol and other anti-mycobacterial drugs, and the combined application with streptomycin, rifampin and fluoroquinolones has synergistic effect.
Aminoglycosides: Streptomycin has certain antibacterial activity against NTM and is sometimes used for the treatment of NTM disease; amikacin has strong antibacterial activity against MAC, with MIC value of 2.4-6.2 mg/L. Most MAC strains are sensitive to the serum concentration value that can be reached by amikacin, and amikacin also has certain antibacterial effect on other NTM, and is a common and effective drug for the treatment of NTM disease. The antibacterial activity of amikacin is stronger than that of Mycobacterium turtles.
5, fluoroquinolones: new fluoroquinolones ofloxacin, ciprofloxacin, levofloxacin, gatifloxacin and moxifloxacin have a certain antibacterial effect on NTM, of which moxifloxacin and gatifloxacin have the strongest antibacterial activity, moxifloxacin and gatifloxacin have the most significant effect on MAC, occasional mycobacteria. A newly developed fluoroquinolone drug (DC-159a) showed good antibacterial effect on most NTM.
6. Cefoxitin: Cefoxitin has a strong antibacterial effect on fast-growing mycobacteria such as Mycobacterium avium and Mycobacterium abscessus.0 471 If the MIC value ≤ 16 mg/L is used as the cut-off point for resistance, 99% of Mycobacterium abscessus is sensitive to cefoxitin. Good clinical efficacy has been achieved with cefoxitin-containing regimens for the treatment of highly resistant fast-growing NTM lung disease.
7, other drugs: tetracyclines such as doxycycline and minocycline have some antibacterial activity against Mycobacterium avium, Mycobacterium tortuis, Mycobacterium abscessus and Mycobacterium marinum. The sulfonamides sulfamethoxazole and compound sulfamethoxazole also have some antibacterial effect on Mycobacterium avium, Mycobacterium tortuis, Mycobacterium abscessus and Mycobacterium marinum. Carbapenems imipenem/cistatin have strong antibacterial effects against fast-growing Mycobacterium avium, Mycobacterium tortuis and Mycobacterium abscessus. The new antibiotics tigecycline and linezolid have strong antibacterial effects against Mycobacterium abscessus and others.
The results of drug susceptibility testing of a total of 2275 clinical isolates of 49 NTM in the Netherlands showed that clarithromycin and rifabutin had the strongest antibacterial activity, with 87% and 83% of strains susceptible to them, respectively; while 44%, 37%, 35%, 33%, 32% and 0.5% of strains susceptible to ciprofloxacin, rifampicin, ethambutol, streptomycin, amikacin and isoniazid, respectively.
(C) Treatment of slow-growing NTM disease
1. MAC: MAC tops the list of pathogenic bacteria of NTM disease. Macrolides are the only antimicrobial drugs with definite efficacy in the treatment of MAC disease; therefore, the basic drugs for MAC disease must include clarithromycin or azithromycin.
For patients with nodular lesions in the lungs or bronchiectasis and those who cannot tolerate daily therapy, the recommended regimen is three times weekly: clarithromycin 1000 mg (or azithromycin 500-600 mg), rifampicin 600 mg and ethambutol 25 mg/kg.
For patients with MAC lung disease with fibro-cavitation or with severe nodular lesions and bronchiectasis, a daily regimen is recommended: clarithromycin 500-1000 mg (or 500 mg for those weighing <50 kg) or azithromycin 250-300 mg, rifampicin 450-600 mg (450 mg for those weighing <50 kg) and ethambutol 15 mg/kg. Amikacin or streptomycin may be considered 3 times a week for 2 to 3 months at the beginning of treatment.
The recommended regimen for patients with severe progressive lesions or who have received treatment is clarithromycin 500-1000 mg/d (500 mg for those weighing <50 kg), or azithromycin 250-300 mg/d, rifabutin 150-300 mg/d (150 mg for those weighing <50 kg), or rifampin 450-600 mg/d (450 mg for those weighing <50 kg 450 mg), ethambutol 15 mg.kg-1.d-1, and amikacin or streptomycin applied 3 times a week for 2 to 3 months at the beginning of treatment.
For patients with macrolide resistant MAC disease, the recommended regimen is amikacin or streptomycin, isoniazid, rifabutin, or rifampin and ethambutol.
The recommended regimen for patients with disseminated MAC disease is: clarithromycin 1000 mg/d or azithromycin 250-300 mg/d, rifabutin 300 mg/d and ethambutol 15 mg.kg-1.d-1. The interaction between macrolides and rifabutin should be concerned, as macrolides can cause increased plasma concentrations of rifabutin, while rifabutin can decrease macrolide If patients experience significant arthralgia, uveitis, neutropenia and hepatic impairment during treatment, rifabutin should be reduced or discontinued. It should also be noted that rifabutin is a weak inducer of hepatic cytochrome P450 isoenzymes and may interact with anti-HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors and should be reduced when used in combination.
In patients with acquired immunodeficiency syndrome (AIDS) combined with disseminated MAC disease, anti-mycobacterial therapy should be continued until 1 year after their immune function is restored, or even for life.
Surgical treatment is recommended for patients with focal unilateral pulmonary lesions that are not effective after medical treatment, resistant to macrolides, and with complications such as hemoptysis, and the drug can be discontinued 1 year after negative sputum mycobacterial culture results after surgery.
Recently, an allergic pulmonary syndrome associated with NTM, especially MAC, has received widespread attention. “The disease is a specific manifestation of MAC lung disease, with a subacute onset and the main symptoms being cough, shortness of breath and fever. Patients are mostly young and non-smokers. Chest X-ray shows diffuse nodular infiltrates and ground glass-like changes. Histopathological examination shows non-necrotizing granulomas and mechanized pneumonia. The key to stopping the progression of allergic lung disease is to avoid exposure to allergens. In patients with severe disease or with respiratory failure, corticosteroid therapy can be given promptly. 3-6 months of short course of antimicrobial drug therapy is effective, the patient’s symptoms can disappear rapidly and the prognosis is good.
2, Mycobacterium kansasii disease: Mycobacterium kansasii disease is second only to MAC disease in the United States, and is also more common in Europe, Asia and Africa. In vitro experimental results show that the majority of Mycobacterium kansasii is sensitive to rifampin, moderately sensitive to isoniazid, ethambutol and streptomycin, macrolides and moxifloxacin also have good antibacterial activity. The recommended daily regimen for Mycobacterium kansasii pneumonia is: rifampin 10 mg/kg (maximum 600 mg), isoniazid 5 mg/kg (maximum 300 mg), ethambutol 15 mg/kg for 12 months until negative sputum culture results; for patients with rifampin-resistant Mycobacterium kansasii pneumonia, a regimen of three to four drugs based on in vitro drug sensitivity testing is recommended A regimen consisting of clarithromycin or azithromycin, moxifloxacin, ethambutol, sulfamethoxazole or streptomycin is recommended until sputum culture results are negative for 12-15 months. The treatment plan for disseminated Mycobacterium kansasii disease is the same as that for Mycobacterium kansasii pneumonia, and in case of AIDS combined with disseminated Mycobacterium kansasii disease, the treatment plan is the same as that for disseminated MAC disease.
In recent years, Mycobacterium haemophilum has also become an important strain causing skin lesions. Mycobacterium haemophilus can cause disseminated lesions in patients with organ transplantation, bone marrow transplantation, AIDS, and long-term corticosteroid use. There is a lack of standard in vitro drug sensitivity testing methods for Mycobacterium haemophilum. It has been reported in the literature that amikacin, clarithromycin, ciprofloxacin, rifampicin and rifabutin have some antibacterial effect on Mycobacterium haemophilum in vitro, and in vitro experiments with doxycycline and sulfonamides have yielded mixed results and are resistant to ethambutol. Recommended treatment regimen: Clarithromycin, rifampicin or rifabutin and ciprofloxacin for 12 months. Surgical treatment is recommended for patients with immunocompromised Mycobacteriophage lymphadenopathy.
4. Mycobacterium ulcerans disease: In recent years, there has been a significant increase in NTM disease caused by Mycobacterium ulcerans, which is the 3rd common mycobacterial pathogen infecting immunocompetent people after MTB and Mycobacterium leprae. Mycobacterium ulcerans can cause necrotic lesions of the skin and soft tissues as well as bone, histologically called Buruli ulcer, and Mycobacterium ulcerans disease has become an important public health problem threatening human health. Recommended treatment regimen: 8 weeks of treatment with clarithromycin and rifampin, which can be supplemented by surgical debridement and skin grafting for those with poor outcomes.
5, sea mycobacteriosis: sea mycobacterium is the main strain of NTM skin disease, and is an important cause of “swimming pool granuloma” or “fish tank granuloma”. The clinical manifestations of Mycobacterium marinum disease are mainly chronic skin, soft tissue and bone disease, starting with skin papules, followed by superficial ulcers and scar formation, mainly on the extremities, such as elbows, knees and the backs of hands and feet. In vitro drug sensitivity tests showed that Mycobacterium marinum was sensitive to rifampicin, rifabutin and ethambutol, moderately sensitive to streptomycin, resistant to isocoumarin and pyrazinamide, more sensitive to clarithromycin and sulfonamides, and moderately sensitive to doxycycline and minocycline. Recommended treatment regimen: rifampin or rifabutin, ethambutol and clarithromycin for 4-6 months. Surgical debridement can be used for those with poor efficacy.
6. Mycobacterium toaderium disease: Mycobacterium toaderium is the 2nd most common pathogen causing NTM disease in Canada and the United Kingdom in Europe. Mycobacterium toadum is widely present in water, soil, tap water systems and showerheads and causes mainly pulmonary disease, but can also cause spinal cord lesions, skin soft tissue lesions and osteoarthrosis in hospitals. Recommended treatment plan: treatment with clarithromycin, rifampin and ethambutol for 12 months after negative sputum culture results; surgical treatment can be considered for those with poor drug efficacy and good lung function.
7, Mycobacterium marmorei disease: In Northern Europe, Mycobacterium marmorei is the 2nd most common NTM pathogen after MAC; in Europe, the clinical relevance of Mycobacterium marmorei isolates is 70% to 80%. Mycobacterium malmoides often causes pulmonary and lymphadenopathy and can also cause disseminated and extrapulmonary Mycobacterium malmoides Mycobacterium malmoides drug sensitivity test results are highly variable and do not correlate well with clinical outcomes. Recommended treatment regimen: treatment with clarithromycin, rifampin, ethambutol, and isoniazid, with the addition of quinolones if necessary, for a period of 12 months after negative sputum culture results.
8. Mycobacterium scrofula disease: Mycobacterium scrofula can cause lymphadenopathy, disseminated mycobacterium scrofula disease, pulmonary disease, skin and soft tissue disease in children. Drug sensitivity test results show that Mycobacterium scrofula is one of the more resistant strains of NTM. Recommended treatment regimen: treatment with regimens containing clarithromycin, ciprofloxacin, rifampin or rifabutin, and ethambutol for 18 to 24 months. Surgical removal of local lesions may be undertaken.
(D) Treatment of fast-growing NTM disease
1, Mycobacterium abscessus disease: In the United States, Mycobacterium abscessus is the 3rd most common pathogen causing NTM lung disease, accounting for 80% of fast-growing NTM lung disease. Mycobacterium abscessus is also a major pathogen causing skin, soft tissue, and bone disease, and is resistant to anti-tuberculosis drugs. In vitro drug sensitivity tests have shown that Mycobacterium abscessus is sensitive to clarithromycin, amikacin and cefoxitin, and moderately sensitive to linezolid, tigecycline, imipenem and clofazimine. The recommended treatment regimen for Mycobacterium abscessus pulmonary disease: 1 macrolide in combination with 1 or more intravenous drugs, such as amikacin, cefoxitin or imipramine, for 6 months. For patients with limited lung lesions and who can tolerate surgery, surgical treatment can be used simultaneously to improve the cure rate. Recommended treatment regimen for Mycobacterium abscessus skin, soft tissue and bone disease: clarithromycin 1000 mg/d or azithromycin 250 mg/d, amikacin 10-15 mg/d, cefoxitin 12 g/d (given in divided doses) or imipramine 500 mg (given in divided doses) for at least 4 months for severe cases and at least 6 months for patients with bone disease, and for patients with extensive lesions, abscess For extensive lesions, abscess formation and poor drug efficacy, surgical debridement or foreign body removal treatment can be adopted.
2, Mycobacterium tortuosum disease: Mycobacterium tortuosum often causes skin, soft tissue and bone disease, and can cause disseminated Mycobacterium tortuosum disease in patients with impaired immune function. Mycobacterium tortuis isolates are sensitive to tobramycin, clarithromycin, linezolid and imipramine, moderately sensitive to amikacin, clofazimine, doxycycline and quinolones, and resistant to cefoxitin. Recommended treatment regimen for Mycobacterium tortuis skin, soft tissue and bone disease: at least 2 sensitive drugs, such as tobramycin, clarithromycin and quinolones, based on the results of in vitro drug sensitivity tests, for at least 4 months, and for at least 6 months for patients with bone disease, with surgical debridement or foreign body removal treatment for extensive lesions, abscess formation and poor drug treatment. The recommended treatment regimen for Mycobacterium tortuosum pneumonia: clarithromycin plus 1 sensitive drug for 12 months after negative sputum culture results.
3, occasional mycobacteriosis: occasional mycobacteria often cause skin, soft tissue and bone disease, occasional mycobacterial pneumopathy is less common, but is more common in patients with chronic gastroesophageal reflux. Mycobacterium avium is the most sensitive to antituberculosis drugs among fast-growing mycobacteria, and is sensitive to macrolides, quinolones, rifampin or rifabutin, sulfonamides, minocycline, doxycycline, cefoxitin, imipramine, and amikacin. Recommended treatment regimen for Mycobacterium avium skin, soft tissue and bone disease: at least 2 sensitive drugs such as quinolones, rifampin or rifabutin and clarithromycin or amikacin for at least 4 months and at least 6 months for bone disease based on in vitro drug sensitivity test results, surgical debridement or foreign body removal for those with extensive lesions, abscess formation and poor drug efficacy, occasional The recommended treatment regimen for Bifidobacterium pneumonia: clarithromycin plus 1 sensitive drug for 12 months after negative sputum culture results.