肺部不常见的非结核分枝杆菌的管理共识及建议(英文版)

不太常见的非结核分枝杆菌肺部疾病的共识管理建议（可用浏览器右键翻译直接查看，比PDF方便）

美国胸科学会、欧洲呼吸学会、欧洲临床微生物学和传染病学会、美国传染病学会2020年非结核分枝杆菌肺病（NTM-PD）治疗临床实践指南；英国胸科学会的 2017 年管理指南涵盖了由鸟分枝杆菌复合体、堪萨斯分枝杆菌、异种分枝杆菌和脓肿分枝杆菌引起的成人肺部疾病。为了提供基于证据的建议，用于治疗没有囊性纤维化或 HIV 感染的成人患者中不太常见的非结核分枝杆菌 (NTM)，我们的专家小组进行了系统的文献检索，为另外七种微生物引起的肺部疾病提供管理指导：龟分枝杆菌、偶发分枝杆菌、热分枝杆菌、戈登分枝杆菌、马尔默分枝杆菌、模拟分枝杆菌和舒尔盖分枝杆菌。治疗建议是通过结构化的共识过程制定的。以英文发表的关于其他 NTM 物种引起的肺部疾病治疗建议的科学文献的证据质量非常低，除 M malmoense 外，并且基于对病例报告和病例系列的评估。对于 M malmoense，两项随机对照试验和三项回顾性队列研究的结果为治疗建议提供了更好的证据基础

Summary

The 2020 clinical practice guideline for the treatment of non-tuberculous mycobacterial pulmonary disease (NTM-PD) by the American Thoracic Society, European Respiratory Society, European Society of Clinical Microbiology and Infectious Diseases, and Infectious Diseases Society of America; and the 2017 management guideline by the British Thoracic Society covered pulmonary diseases in adults caused by Mycobacterium avium complex, Mycobacterium kansasii, Mycobacterium xenopi, and Mycobacterium abscessus. In order to provide evidence-based recommendations for the treatment of less common non-tuberculous mycobacterial (NTM) species in adult patients without cystic fibrosis or HIV infection, our expert panel group performed systematic literature searches to provide management guidance for pulmonary diseases caused by seven additional organisms: Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium genavense, Mycobacterium gordonae, Mycobacterium malmoense, Mycobacterium simiae, and Mycobacterium szulgai. Treatment recommendations were developed by a structured consensus process. The evidence from the scientific literature published in English for treatment recommendations for pulmonary diseases caused by other NTM species was of very low quality, with the exception of M malmoense, and based on the evaluation of case reports and case series. For M malmoense, results from two randomised controlled trials and three retrospective cohort studies provided a better evidence base for treatment recommendations, although the evidence was still of low quality.

Introduction

The 2020 updated management guideline for patients with non-tuberculous mycobacterial pulmonary diseases (NTM-PD) focuses on population, intervention, comparison, and outcome question-guided management recommendations for pulmonary disease in adults caused by Mycobacterium avium complex, Mycobacterium kansasii, Mycobacterium xenopi, and Mycobacterium abscessus.1, 2 However, management options for NTM-PD caused by other clinically relevant non-tuberculous mycobacteria (NTM) covered in the previous management guideline are also needed for the care of affected patients.³ At present, treatment recommendations for patients with other NTM-PDs are primarily based on expert opinions and often variable. Health-care providers of patients with NTM-PDs should consult with a clinical microbiologist who has expertise in identification and antimycobacterial drug susceptibility testing, and a clinician with expertise in managing NTM disease. However, evidence-based management decisions are needed for patients affected by NTM not covered in the 2017 guideline by the British Thoracic Society (BTS) or the 2020 American Thoracic Society (ATS), European Respiratory Society (ERS), European Society of Microbiology and Clinical Infectious Diseases (ESCMID), and Infectious Diseases Society of America (IDSA) guideline.⁴

The panel of members of the 2020 ATS, ERS, ESCMID, and IDSA guideline committee did systematic reviews of the literature, independently of the societies involved in the original task force, to provide management guidance for pulmonary diseases caused by seven additional organisms: Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium genavense, Mycobacterium gordonae, Mycobacterium malmoense, Mycobacterium simiae, and Mycobacterium szulgai.

The following consensus guidance includes recommendations for antibiotics guided by in-vitro susceptibility results. With the exception of M chelonae and M fortuitum, there are no validated break points defining susceptibility and resistance for any of the antibiotics used for the organisms considered here.⁵

Methods

A search (see appendix pp 4–7) was adapted for execution on the Ovid MEDLINE platform and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Embase, and the Cochrane Central Register of Controlled Trials. Searches were limited to human studies or studies indexed with neither human nor animal and those published in English. A final update was executed on Jan 6, 2020. Teams of two or three independent experts evaluated the search results for eligibility; they supplemented the electronic search by contacting experts and handsearching journals, conference proceedings, reference lists, and regulatory agency websites for relevant articles.

In addition to the systematic reviews, the members of the panel ascertained agreement on management options in a six-step consensus process as previously published.6, 7, 8 The results of the panel experts' votes, either in favour or against the treatment approach, is presented in the appendix (appendix p 1).

General recommendations

The expert panel recommends that health-care providers consult with a clinical microbiologist who has expertise in identification and antimycobacterial drug susceptibility testing. Patients should be referred to a clinician with expertise in managing NTM-PD before treatment against any of the mycobacterial pathogens described in this consensus document is initiated. The clinical and microbiological criteria for the diagnosis of NTM-PD are displayed in panel.

Panel

Clinical and microbiological criteria for diagnosis of non-tuberculous mycobacteria

Clinical

Pulmonary or systemic symptoms; and nodular or cavitary opacities on chest radiograph or a high-resolution computed tomography scan that shows bronchiectasis with multiple small nodules and appropriate exclusion of other diagnoses.

Microbiological*•

Positive culture results for a non-tuberculous mycobacteria (NTM) from at least two separate expectorated sputum samples. If the results are nondiagnostic, consider repeat sputum acid-fast bacilli smears and cultures.

or•

Positive culture results for a NTM from at least one bronchial wash or lavage.

or•

Transbronchial or other lung biopsy with mycobacterial histologic features (granulomatous inflammation or acid-fast bacilli) and positive culture for NTM or biopsy showing mycobacterial histologic features (granulomatous inflammation or acid-fast bacilli) and one or more expectorated sputum or bronchial washings that are culture positive for NTM.

Expert consultation should be obtained when NTM are recovered that are either infrequently encountered or that usually represent environmental contamination. Patients who are suspected of having NTM pulmonary disease but do not meet the diagnostic criteria should be followed up until the diagnosis is firmly established or excluded. Making the diagnosis of NTM pulmonary disease does not per se, necessitate the institution of therapy, which is a decision based on the potential risks and benefits of therapy for individual patients.

The choice of treatment regimen should be guided by the results of the antimycobacterial drug susceptibility testing, although for some species causing NTM-PD—ie, M genavense and M simiae—the correlation of antimycobacterial drug susceptibility testing and clinical outcome can be poor (figure). For orientation, the minimum inhibitory concentrations (MIC) of antibiotics against select NTM species required to inhibit the growth of 50% and 90% of organisms (MIC50 and MIC90) are provided in the appendix (appendix p 2). The major contributions of the mycobacteriology laboratory are to correctly identify the NTM species, perform antimycobacterial drug susceptibility testing, and detect acquired and inducible resistance. The dosing of drugs for the treatment of NTM-PDs mentioned in this document follows recent ATS, ERS, ESCMID, and IDSA recommendations (table 1).1, 2 Treatment considerations are summarised in Table 2, Table 3 and the quality of the evidence and strength of the recommendations are displayed in the appendix (appendix p 3)

Table 1. Dosing guidelines for drugs used in the management of NTM-PD

Empty Cell	Daily dose	Three times a week dose	Hepatic impairment dose	Renal impairment dose
Oral
Azithromycin	250–500 mg once a day	500 mg once a day	NA	NA
Ciprofloxacin	500–750 mg twice a day	NA	NA	250–500 mg dosed at intervals according to CrCl
Clarithromycin	500 mg twice a day	500 mg once a day	NA	Reduce dose by 50% if CrCl less than 30 mL/min
Clofazimine*	100–200 mg once a day	NA	Caution in severe hepatic impairment	NA
Doxycycline	100 mg once a day or twice a day	NA	NA	NA
Ethambutol	15 mg/kg once a day	25 mg/kg once a day	NA	Increase dosing interval (eg, 15–25 mg/kg, three times a week)
Levofloxacin	750–1000 mg once a day	NA	NA	Increase dosing interval (eg, 10–15 mg/kg, three times a week)
Linezolid	600 mg once a day or twice a day†	NA	NA	NA
Moxifloxacin	400 mg once a day	NA	NA	NA
Rifabutin	150–300 mg once a day (150 mg once a day with clarithromycin)	300 mg once a day	Caution	Reduce dose by 50% if CrCl less than 30 mL/min
Rifampicin	10 mg/kg (450 mg or 600 mg) once a day	600 mg once a day	Caution	NA
Co-trimoxazole	800 mg trimethoprim and 160 mg sulfamethoxazole twice a day	NA	Caution	Reduce dose by 50% if CrCl 15–30 mL/min
Parenteral
Amikacin‡ (IV)	15–20 mg/kg once a day§, adjusted according to drug level monitoring¶	15–25 mg/kg once a day§, adjusted according to drug level monitoring¶	NA	Reduce dose or increase dosing interval (eg, 15 mg/kg, twice a week or three times a week)
Cefoxitin (IV)	2–4 g twice a day or three times a day (maximum daily dose is 12 g/day)	NA	NA	Reduce dose or increase dosing interval
Imipenem-cilastatin (IV)	1g each, twice a day or three times a day	NA	NA	Reduce dose or increase dosing interval
Tobramycin‡ (IV)	4.5–7 mg/kg once a day	5–7 mg/kg once a day	NA	Reduce dose or increase dosing interval (eg, 5–7 mg/kg, twice a week or three times a week); inhalative route of administration not studied

NA=not applicable. NTM-PD= non-tuberculous mycobacterial pulmonary disease. CrCl= creatinine clearance. IV=intravenously. This table should be considered as a general guide for dosing in clinical practice, and it does not replace specific local, national, or regional dosing guidelines.*

Clofazimine availability varies by country. In the USA, an investigational new drug application is required.†

Most experts recommend once a day dosing of linezolid because of the high rate of drug-related adverse reactions associated with twice a day dosing.‡

Caution must be exercised in the prolonged use of aminoglycosides because of the risk of otovestibular toxicity and nephrotoxicity.§

The use of the described regimens for 15 weeks was associated with permanent ototoxicity in approximately a-third of patients, and the risk was associated with age and cumulative dose. Given the high rates of ototoxicity, risks and benefits should be carefully considered with the aims of therapy. Clinicians should consider lower dose ranges and probably rely on intermittent dosing when more prolonged therapy is employed.¶

Drug level monitoring: trough less than 5 mg/L, peak with daily dosing 35–45 μg/mL, peak with intermittent dosing 65–80 μg/mL.

Table 2. Treatment regimens for rapidly growing NTM-PD

Empty Cell	Number of drugs	Drugs	Duration of therapy	Comments
M chelonae	Initial phase (≥3); continuation phase (≥2)	Azithromycin (once a day) or clarithromycin (twice a day); tobramycin IV (once a day or three times a week); imipenem-cilastatin (two to three times a day); moxifloxacin (once a day) or levofloxacin (once a day), or ciprofloxacin (twice a day); linezolid (once a day); clofazamine (once a day)	12 months beyond culture conversion	Very low level of evidence; drugs should be selected according to DST results when available; caution patients about aminoglycoside ototoxicity and nephrotoxicity; for mild to moderate disease an oral two-drug regimen could suffice, provided that DST has proven two such drugs to be active
M fortuitum	Initial phase (≥3); continuation phase (≥2)	Moxifloxacin (once a day) or levofloxacin (once a day), or ciprofloxacin (twice a day); amikacin IV (once a day or three times a week); imipenem-cilastatin (two to three times a day); cefoxitin (two to three times a day); linezolid (once a day); co-trimoxazole (twice a day); (clofazimine [once a day]); (doxycycline [twice a day])*	12 months beyond culture conversion	Very low level of evidence; drugs should be selected according to DST results when available; the detection and management of underlying oesophageal disorders or aspiration is critical; fluoroquinolones are probably the most effective; there is natural resistance to macrolides; caution patients about ototoxicity and nephrotoxicity of aminoglycosides; for mild to moderate disease an oral two-drug regimen could suffice provided that DST has proven two such drugs to be active

NTM-PD=non-tuberculous mycobacterial pulmonary disease. IV=intravenously. DST=drug susceptibility testing.*

Drugs in brackets are non-preferred options.

Table 3. Treatment regimens for slowly growing NTM-PD

Empty Cell	Number of drugs	Drugs*	Duration of therapy	Comments
M genavense	≥3	Azithromycin (once a day) or (clarithromycin [twice a day]); rifampicin (once a day); ethambutol (once a day); (moxifloxacin [once a day]); (clofazimine [once a day]); (amikacin IV [once a day])	12 months beyond culture conversion	Very low level of evidence; drugs should be selected according to DST results when available; moxifloxacin or amikacin may be used in cases of intolerance or drug resistance to macrolides, rifamycins, or ethambutol
M malmoense	≥3	Azithromycin (once a day) or (clarithromycin [twice a day]); rifampicin (once a day); ethambutol (once a day); (amikacin IV [once a day or three times a week]); (moxifloxacin [once a day]); (clofazimine [once a day])	12 months beyond culture conversion	Low level of evidence; drugs should be selected according to DST results, when available; moxifloxacin or clofazimine can be used in case of intolerance or drug resistance to macrolides, rifamycins, or ethambutol; amikacin should be added for cavitary or severe disease; caution patients about aminoglycoside ototoxicity and nephrotoxicity
M szulgai	≥3	Azithromycin (once a day) or (clarithromycin [twice a day]); rifampicin (once a day); ethambutol (once a day); (moxifloxacin [once a day]); (clofazimine [once a day]); (amikacin IV [once a day or three times a week])	12 months or 12 months beyond culture conversion if treatment with a macrolide, a rifamycin, or ethambutol cannot be used.	Very low level of evidence; drugs should be selected according to DST results, when available; fluoroquinolones (moxifloxacin or levofloxacin), clofazimine, or aminoglycosides (streptomycin or amikacin) can be used in case of intolerance or drug resistance to macrolides, rifamycins, or ethambutol; caution patients about ototoxicity and nephrotoxicity of aminoglycosides
M simiae	≥3	Azithromycin or (clarithromycin); moxifloxacin (once a day); co-trimoxazole (twice a day); clofazimine (once a day); (amikacin IV [once a day or three times a week])	12 months beyond culture conversion	Very low level of evidence; drugs should be selected according to DST results, when available; amikacin should be added for cavitary or severe disease; possible combinations include azithromycin, moxifloxacin, and co-trimoxazole; azithromycin, clofazimine, and amikacin; or azithromycin and moxifloxacin in combination with one or two additional drugs based on DST results with clofazimine and amikacin being the most suitable options
M gordonae†	NA	NA	NA	NA

IV=intravenously. DST=drug susceptibility testing. NA=not applicable.*

Drugs in brackets are non-preferred options.†

In general, isolation of M gordonae from respiratory specimens represents transient colonisation or laboratory contamination; treatment should not be offered without overwhelming evidence that this organism is causing invasive pulmonary disease. If treatment is necessary, DST can be performed; although no standard treatment can be recommended, a combination of a macrolide, rifampicin, and ethambutol has been described as successful.

To monitor treatment (supplement table 2, appendix p 3), sputum samples should be collected for culture every 1–2 months after initiation of therapy until there is sputum conversion to culture negative (at least two consecutive negative mycobacterial sputum cultures, collected at least 4 weeks apart during antibiotic treatment); the sampling date of the first negative culture is the date of sputum conversion to culture negative.⁶ Thereafter, sputum should be collected every 2–3 months until therapy is completed, defined as 12 months of negative mycobacterial sputum cultures (while on therapy) from the date of the first negative culture.

Rapidly growing NTM

M chelonae

M chelonae is an unusual cause of NTM-PD;3, 9, 10 therefore, clinicians should carefully assess for other causes of the patients symptoms and verify fulfillment of disease criteria before embarking on a course of treatment. Isolates are usually susceptible to tobramycin, macrolides (eg, clarithromycin and azithromycin), clofazimine, linezolid, and sometimes to fluoroquinolones and imipenem.3, 11, 12, 13, 14, 15 Tobramycin is more active in vitro than amikacin and M chelonae is generally resistant to cefoxitin.¹⁶ M chelonae does not contain an erythromycin resistance methylase (erm) gene,¹⁷ so the macrolides are considered fully active, unlike M fortuitum and some M abscessus subspecies, which have functional erm genes. Antimycobacterial drug susceptibility testing should be done, as well as detection of acquired resistance to macrolides, which was described in this species, although mostly in non-pulmonary infections.¹⁸

A systematic literature review by two independent experts identified 18 case reports and case series describing 57 patients with M chelonae pulmonary disease in the scientific literature published in English, but no evidence-based management recommendations for M chelonae pulmonary disease based on clinical trial data.9, 14, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 In most patients, risk factors for M chelonae pulmonary disease were not stated or could not be identified. Approximately 15% of patients who have been reported with M chelonae pulmonary disease were post-organ transplant.19, 21, 23 By contrast with M fortuitum pulmonary disease, gastrointestinal motility disorders (eg, achalasia) did not appear to be a prominent risk factor for M chelonae pulmonary disease. The clinical spectrum of M chelonae pulmonary disease includes bronchiolitis, fibronodular or patchy consolidations, cavitary disease, and rarely empyema.

Treatment for M chelonae pulmonary disease initially includes at least two drugs for mild to moderate disease or three drugs in more severe disease that the organism shows in-vitro susceptibility to. Treatment often includes one or two intravenous drugs to be continued for an initial period, usually for 4–16 weeks, to achieve control of disease; tobramycin is the preferred aminoglycoside. At least two oral drugs, one of which should be a macrolide that has demonstrated in-vitro susceptibility, are administered for a total duration of therapy of at least 12 months after conversion to culture negative, to complete the treatment regimen.

Favoured antibiotics include azithromycin (250–500 mg) once a day or clarithromycin (500 mg) twice a day, tobramycin (4·5–7 mg/kg) intravenously once a day or tobramycin (5–7 mg/kg) intravenously three times a week, imipenem-cilastatin (1 g each) intravenously two or three times a day or a fluoroquinolone—eg, moxifloxacin (400 mg) once a day—clofazimine (100–200 mg) once a day, or linezolid (600 mg) once a day, based on in-vitro antimycobacterial drug susceptibility test results. Caution must be exercised in the prolonged use of aminoglycosides because of the risk of otovestibular toxicity and nephrotoxicity. Approximately 20% of patients with M chelonae pulmonary disease received adjunctive partial pulmonary surgical resection;20, 25 these patients generally had a successful treatment outcome, thus surgical resection should be considered when it is an option. Based on the available literature, it was not possible to state an association between the type of drug therapy against M chelonae pulmonary disease and successful treatment outcome.

M fortuitum

Although M fortuitum is a relatively common NTM species isolated from respiratory specimens, it is a relatively uncommon cause of NTM-PD.3, 9, 35 Clinicians should maintain a high-diagnostic threshold for identifying M fortuitum pulmonary disease, and they should carefully assess for other causes of the patients symptoms and radiological abnormalities. M fortuitum isolates are usually susceptible to multiple antibiotics including fluoroquinolones, doxycycline, minocycline, and sulfonamides.³ In-vitro data suggest susceptibility to clofazimine (appendix p 2). In addition, isolates are typically susceptible to amikacin and imipenem. M fortuitum usually contains an erm (39) gene which confers inducible resistance; therefore, macrolides should not be considered active.³⁶ Antimycobacterial drug susceptibility testing should be done, as well as detection of acquired resistance to fluoroquinolones, which was described in this species, although mostly in non-pulmonary infections.³⁷

A systematic literature review by two independent experts identified 45 case reports and case series describing 150 patients with M fortuitum pulmonary disease in the scientific literature published in English, but no evidence-based management recommendations based on clinical trial data for M fortuitum pulmonary disease.11, 19, 21, 24, 26, 28, 29, 31, 32, 34, 35, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71

M fortuitum pulmonary disease occurs predominantly in patients with underlying conditions: oesophageal and gastrointestinal motility problems (eg, achalasia),40, 41, 45 structural lung changes such as post-tuberculosis changes35, 38, 54 severe chronic obstructive pulmonary disease (COPD),58, 69 and cancer.24, 58 Conversion to sputum culture negative for M fortuitum without antibiotic treatment is not uncommon when the underlying cause (eg, achalasia) has been addressed.⁹ The underlying cause must be addressed if possible; with its correction or improvement, antibiotic treatment might not be required, or a less intensive regimen might suffice. However, M fortuitum pulmonary disease is associated with a poor prognosis and about a-third of the affected patients reported in the literature do not survive despite antibiotic therapy, probably reflecting the severity of the underlying disease.28, 45, 58, 68, 71

Patients who received fluoroquinolones as part of their treatment regimen seemed to have a favourable treatment outcome, but we did not find any publications that met the criteria of a clinical trial for evidence-based management recommendations for M fortuitum pulmonary disease.38, 42, 53, 54, 56, 58, 63, 67

Clinicians should be aware that there are other mycobacterial species related to M fortuitum (Mycobacterim peregrinum, Mycobacterim septicum, Mycobacterim porcinum, and Mycobacterim conceptionense) included in the so-called M fortuitum complex, which might present different antibiotic susceptibilities, including macrolide susceptibility.⁷²

Treatment for M fortuitum pulmonary disease should include at least two drugs for mild-to-moderate disease or three drugs in more severe disease that the organism shows in-vitro susceptibility to. Treatment often includes one or two intravenous drugs to be continued for an initial period, usually for 4–16 weeks, to achieve control of disease; amikacin is the preferred aminoglycoside. Frequently used doses include amikacin (15–20 mg/kg) intravenously once a day or amikacin (15–25 mg/kg) three times a week in severe disease manifestations (lower in older patients and in prolonged treatment). Caution must be exercised in the prolonged use of aminoglycosides because of the risk of otovestibular toxicity and nephrotoxicity. Other favoured intravenous drugs are imipenem-cilastatin (1 g each) intravenously two or three times a day or cefoxitin (3–4 g) intravenously twice a day. At least two oral drugs that have demonstrated in-vitro susceptibility should be continued until at least 12 months after conversion to culture negative to complete the treatment regimen. Favoured oral antibiotics include fluoroquinolones—eg, moxifloxacin (400 mg) once a day or levofloxacin (750–1000 mg) once a day—co-trimoxazole (trimethoprim 800 mg and 160 mg sulfamethoxazole) twice a day, linezolid (600 mg) once a day, clofazimine (100–200 mg) once a day, or doxycycline (100–200 mg) once a day. A summary of rapidly growing NTM treatment recommendations is shown in table 2.

Slowly growing NTM

M genavense

M genavense is a rare cause of NTM-PD.73, 74, 75 The organism is fastidious and does not grow on solid media, although limited growth can be observed in supplemented broth cultures; molecular detection is most reliable, thus antimycobacterial drug susceptibility testing in M genavense is challenging.⁷⁶ A systematic literature review by two independent experts identified five case reports and case series describing six patients with M genavense pulmonary disease in the scientific literature published in English, but no clinical trial data to inform evidence-based management recommendations for M genavense pulmonary disease.73, 77, 78, 79 M genavense was first described in the setting of severe immunosuppression with disseminated disease.3, 74, 75, 80

Available data suggests that most isolates are susceptible in vitro to fluoroquinolones, clofazimine, and amikacin, although susceptibility testing has not been standardised for M genavense (appendix p 2).80, 81 Case series have described treatment success with macrolide containing multi-drug regimens that typically include ethambutol plus one or two other drugs such as a rifamycin, amikacin, or a fluoroquinolone.74, 75, 82, 83, 84

Treatment for M genavense pulmonary disease includes at least three drugs that the organism shows in-vitro susceptibility to. The panel suggests the following treatment regimen: azithromycin (250–500 mg) once a day, rifampicin (600 mg) once a day, and ethambutol (15 mg/kg) once a day. In case of intolerance or drug resistance to macrolides, rifamycins, or ethambutol, the following treatment regime can be used instead: moxifloxacin (400 mg) once a day, amikacin (15–20 mg/kg) intravenously once a day or amikacin (15–25 mg/kg) three times a week (lower in older patients and prolonged use), or clofazimine (100–200 mg) once a day. Treatment should be continued until at least 12 months post-conversion to culture negative to complete the treatment regimen.

M gordonae

M gordonae is known as a non-pathogenic species but is one of the most common NTM isolated from respiratory samples; probably because it is prevalent in the environment, especially the water supply network.85, 86, 87, 88, 89 It is also easily isolated in mycobacteriology laboratories (naturally orange colonies growing on all media after 2 weeks incubation). Limited data suggest that M gordonae is variably susceptible in vitro to several agents: clarithromycin, ciprofloxacin, linezolid, and amikacin.90, 91, 92 The correlation between these in-vitro results and patient outcomes is unknown.

A systematic literature review by two independent experts identified nine case reports and case series describing 13 non-immunosuppressed adults with M gordonae pulmonary disease in whom treatment and outcomes were adequately described, but no evidence-based management recommendations for M gordonae pulmonary disease based on clinical trial data.69, 93, 94, 95, 96, 97, 98, 99, 100

Treatment for M gordonae pulmonary disease before 1990 often included isoniazid, rifampicin, and ethambutol. Treatment in newer studies more frequently included clarithromycin, rifampicin, and ethambutol. Information regarding cure was provided for 12 cases and was definite or likely in 11 (92%) patients overall and 11 patients who did not experience respiratory failure.69, 93, 94, 95, 96, 97, 98, 99, 100 Surgical resection, in addition to antibiotic therapy, was described in two patients, both of whom were cured.97, 100

When M gordonae is cultured in respiratory samples, other causes of lung disease should be carefully considered. Multiple sputum samples should be collected over several weeks or months to identify the presence of any other NTM known to be more pathogenic. Clinicians should maintain a high-diagnostic threshold for identifying M gordonae pulmonary disease. In addition to the clinical and radiological criteria for M gordonae pulmonary disease (as M gordonae is almost always non-pathogenic) described in the international NTM guidelines,⁹⁷ more than two positive sputum cultures and at least one detection of acid-fast bacilli in a respiratory specimen with documented M gordonae cultures should be present.

Even when current diagnostic criteria are met, treatment is seldom necessary. In the rare situation when treatment is necessary, antimycobacterial drug susceptibility testing can be done as for other NTM; although no standard treatment can be recommended, a combination of a macrolide, rifampicin, and ethambutol has been described as successful in some cases.

M malmoense

M malmoense was first described in four patients from Malmö and Lund, Sweden,¹⁰¹ in 1977 and is one of the most common species causing NTM-PD in regions of northern Europe. Multiple studies using different laboratory methods have described the susceptibility of M malmoense to rifampicin, rifabutin, clarithromycin, and clofazimine, with variable resistance to amikacin, ethambutol, and fluoroquinolones, and resistance to isoniazid.102, 103, 104, 105, 106

M malmoense most commonly causes pulmonary disease but can also cause cervical lymphadenitis, tenosynovitis, skin infections, and rarely disseminated disease in the severely immunocompromised host. It is seldom isolated from the environment but it can be found in natural water and soil in some geographical areas.107, 108, 109 The clinical presentation of M malmoense pulmonary disease frequently mimics tuberculosis, with cavities and airspace disease being the most common radiological findings.110, 111 The majority of affected patients are male, approximately half have underlying COPD or a history of pulmonary tuberculosis. When M malmoense is isolated from respiratory samples, it is usually of clinical significance, although there is some geographical variability suggesting that pathogenicity might vary by region.102, 112

A systematic literature review by two independent experts found five publications (two randomised controlled trials104, 105 and three retrospective cohort studies102, 113, 114) that met criteria for evidence-based management recommendations for M malmoense pulmonary disease. In addition, two systematic reviews were identified that addressed treatment outcomes or treatment recommendations for M malmoense pulmonary disease.4, 48

An early retrospective review¹¹³ from Cardiff, UK, described the clinical outcomes of 37 patients with M malmoense pulmonary disease who were treated with a variety of non-macrolide-based treatment regimens. Those who received three drugs (isoniazid, rifampicin, and ethambutol) for 18–24 months tended to do better than those who received two drugs, or those who were treated for less than 18 months.¹¹³ Among patients treated with a BTS recommended regimen (rifampicin plus different combinations of ethambutol, isoniazid, clarithromycin, or ciprofloxacin) treatment success was achieved in 75% of patients. In a series of 14 consecutive patients with fibrocavitary M malmoense pulmonary disease in Edinburgh, UK, investigators reported 100% conversion to culture negative and symptom reduction after 24 months of combination rifampicin (450–600 mg) once a day, ethambutol (15 mg/kg) once a day, and clarithromycin (500 mg) twice a day.¹¹⁴ In this study initial M malmoense isolates from all 14 patients were judged to be susceptible to rifampicin and resistant to isoniazid, with 23% resistant to ethambutol, 8% resistant to clarithromycin, and 46% resistant to ciprofloxacin. A retrospective review of 30 patients with M malmoense pulmonary disease from the Netherlands found that multi-drug treatment regimens varied considerably, although most received a macrolide in addition to ethambutol and rifampicin.¹⁰² The mean duration of therapy was 12 months, which is shorter than the duration in the BTS trials. 21 (70%) patients had a good clinical response (defined as symptomatic improvement and conversion to culture negative) to treatment, five (17%) patients had failure or relapse, and four (13%) patients died.

The BTS performed a randomised controlled trial involving 106 patients with M malmoense pulmonary disease; patients were treated for 2 years with either rifampicin and ethambutol or rifampicin, ethambutol, and isoniazid.104, 105 Of 106 patients, 10% of patients had a poor clinical outcome (death due to NTM, treatment failure, or relapse); there was no significant difference between groups. Only 20 (38%) of 52 patients who received rifampicin and ethambutol, and 24 (44%) of 54 of patients who additionally received isoniazid were alive and free of relapse, and therefore considered cured after 5 years. A second BTS randomised controlled trial allocated 167 patients to 2 years of treatment with rifampicin, ethambutol, and clarithromycin; or rifampicin, ethambutol, and ciprofloxacin. ¹¹⁵ Although there was no significant difference in the poor outcome rate between groups (overall, 7%), more patients receiving the rifampicin, ethambutol, and clarithromycin regimen completed treatment and were alive and cured at 5 years (38% vs 20%); however, there were more side effects in this group. In addition, the number of patients alive and cured at 5 years in the clarithromycin group was the same as that seen with rifampicin and ethambutol in the previous trial. Compared with patients with M avium complex and M xenopi pulmonary disease, who were also included in the trial, patients with M malmoense were significantly less likely to have a poor outcome.

Two systematic reviews were identified.4, 48 One systematic review reported that three studies105, 114, 115 investigated treatment outcomes in patients with M malmoense pulmonary disease, comprising a total of 287 patients.⁴⁸ The weighted average proportion of treatment success (the proportion of patients in whom sputum conversion to culture negative was achieved at the end of therapy minus the proportion of relapses reported at the end of follow-up) was 54·4% (95% CI 34·7–73·4); however, the authors noted that the comparability between the studies and the different treatment regimens was impeded by the high all-cause mortality of 34–49·1%.

The BTS NTM guideline reviewed two randomised controlled trials104, 115 and four case series.102, 103, 113, 114 For non-cavitary disease the recommended treatment was with a macrolide, rifampicin, and ethambutol. The addition of parenteral or inhaled amikacin was recommended in cavitary disease, although there was no evidence presented that supported the use of amikacin.⁴ A macrolide-containing three-drug regimen offers the best option for treatment success based on these studies, although treatment outcomes remain suboptimal and the evidence base for treatment recommendations is low.

Treatment for M malmoense pulmonary disease generally includes at least three drugs: azithromycin (250–500 mg) once a day or clarithromycin (500 mg) twice a day, rifampicin (600 mg) once a day, and ethambutol (15 mg/kg) once a day. Additional drugs may include moxifloxacin (400 mg) once a day or clofazimine (100–200 mg) once a day. Based on the utility of amikacin for most NTM species (except M chelonae), favourable in-vitro drug susceptibility profiles, and expert opinion, the addition of parenteral amikacin can be considered in severe cases, such as cavitary disease. The optimal duration of therapy is unknown, but consistent with other NTM pulmonary pathogens the expert panel recommends a total duration of therapy of at least 12 months post-conversion to culture negative to complete the treatment regimen.

M simiae

M simiae is a rare human pathogen causing disseminated or pulmonary disease; only 4–21% of patients with respiratory M simiae isolates fulfil the ATS diagnostic criteria.116, 117, 118 The rates of isolation vary geographically¹¹⁹ with higher rates being reported in Israel120, 121, Lebanon¹²², Iran¹²³ and India.¹²⁴ Respiratory isolates of M simiae are most often contaminants, thus clinicians should maintain a high threshold to diagnose M simiae pulmonary disease and carefully assess for other causes of a patient's symptoms or radiological abnormalities. M simiae is considered among the hardest to treat NTM owing to its natural drug resistance; most antimycobacterial drug susceptibility testing reports of M simiae describe resistance to most tested drugs.116, 118, 125 In vitro, the M simiae strain ATCC 25275 was resistant to most of the 19 drugs tested, except macrolides, clofazimine, and sulfamethoxazole (quinolones and aminoglycosides were not tested).¹²⁶ Furthermore, there is in-vitro synergy between clofazimine and amikacin for M simiae isolates.¹¹ In addition, variable proportions of clinical strains can be susceptible to moxifloxacin (and to ciprofloxacin, to a lesser extent), aminoglycosides, and cycloserine.125, 127

A systematic literature review by two independent experts identified 11 case reports and case series describing 197 patients with M simiae pulmonary disease in the scientific literature published in English, but no evidence-based management recommendations for M simiae pulmonary disease based on clinical trial data.116, 117, 121, 122, 128, 129, 130, 131, 132, 133, 134 The largest study of 102 patients was from Israel; no treatment failures or relapses were reported during a mean follow-up of 24 months, with patients receiving clarithromycin, ethambutol, and rifampicin treatment for at least 12 months.¹²¹ Although the 1997 ATS criteria were reportedly used to select patients, 38 (37%) of 102 patients were asymptomatic and had an unremarkable chest radiograph; therefore, not fulfilling these criteria. The expert panel concluded that data from this study could not be considered reliable enough to form a basis for treatment recommendations.¹²¹

The treatment regimen for M simiae pulmonary disease includes at least three drugs: azithromycin (250–500 mg) once a day or clarithromycin (500 mg) twice a day, moxifloxacin (400 mg) once a day, co-trimoxazole (trimethoprim 800 mg and sulfamethoxazole 160 mg) twice a day, amikacin (15–20 mg/kg) intravenously once a day or amikacin (15–25 mg/kg) three times a week (lower in older patients and with prolonged use), or clofazimine (100–200 mg) once a day. Depending on antimycobacterial drug susceptibiltity testing, accepted treatment regimes could be a clofazimine, amikacin, and azithromycin combination or a azithromycin, moxifloxacin, and co-trimoxazole combination,3, 16 or a azithromycin and moxifloxacin combination with one or two additional drugs based on antimycobacterial drug susceptibility testing results; clofazimine and aminoglycosides would be the most appropriate options.¹²⁵ Surgical resection of affected lobes should be evaluated as an adjunctive treatment option.¹⁶ Optimal treatment duration is unknown; experts consider treating for at least 12 months after conversion to negative sputum culture, possibly introducing a step-down approach to consolidation therapy (eg, stop intravenous amikacin) once clinical, microbiological, and radiological improvement has been documented.

M szulgai

M szulgai is an unusual cause of pulmonary disease and accounts for less than 1% of human respiratory isolates of NTM; however, the isolation of M szulgai appears to be clinically relevant in most cases.135, 136, 137 Isolates are usually susceptible in vitro to clarithromycin and rifampicin. The largest case series reporting on antimycobacterial susceptibility testing of M szulgai included 23 strains of M szulgai.¹⁰⁶ Drug resistance was observed in all 23 (100%) strains to isoniazid, in 9% of strains to ethambutol, in 26% of strains to ciprofloxacin, 13% of strains to amikacin, and in 4% of strains to rifampicin. All 23 strains of M szulgai were susceptible to clarithromycin. In-vitro data suggest susceptibility to clofazimine (appendix p 2). Later generation fluoroquinolones were not tested.

A systematic literature review conducted by two independent experts identified 25 retrospective case reports and case series, including a total of 44 patients with M szulgai pulmonary disease described in the scientific literature published in English136, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149 but no evidence-based management recommendations for M szulgai pulmonary disease based on clinical trial data. Most patients were treated with a combination of rifampicin, ethambutol, and clarithromycin or azithromycin. Other treatments included a mixture of rifampicin-based regimens; usually a combination of rifampicin with two or more drugs: isoniazid, ethambutol, fluoroquinolones, ethionamide, and intravenous drugs. Treatment duration was variable; 12 months was most frequently used (range 5–18 months). The outcome was favourable in 85% of patients treated with rifampicin, clarithromycin, and azithromycin combination regimens; no relapses were observed among the five (11%) patients that post-treatment follow-up was available for. The cure rate was 81% among 21 patients treated with clarithromycin and azithromycin sparing regimens; unfavourable outcomes included one failure of treatment after 6 months and one relapse related to non-compliance. Four (9%) patients underwent surgery, but it was only performed to treat M szulgai pulmonary disease in two of these patients, and one of these two patients had a tissue culture sample that was negative for M szulgai.

Treatment for M szulgai pulmonary disease should include at least three drugs that the organism shows in-vitro susceptibility for. Based on the low level evidence available, a combination of rifampicin (600 mg) once a day, azithromycin (250–500 mg) once a day or clarithromycin (500 mg) twice a day, and ethambutol (15 mg/kg) once a day for 12 months is recommended. Clofazimine (100–200 mg) once a day can be used if there is intolerance or drug resistance to macrolides, rifamycins, or ethambutol. Intravenously administered drugs (eg, amikacin) are alternatives in case of intolerance or resistance to the recommended orally available drugs. There are no in-vitro susceptibility data or clinical experience with later-generation fluoroquinolones. In such cases, if a treatment with a macrolide, rifamycin, and ethambutol cannot be used, it is advised to prolong treatment to 12 months after conversion to culture negative. There is no evidence to recommend surgery as part of the treatment for M szulgai pulmonary disease.

A summary of slowly growing NTM treatment recommendations is shown in table 3.

Conclusion

We did a systematic review of the literature and consensus process to provide treatment recommendations for pulmonary diseases caused by seven additional NTM not covered in the recent ATS, ERS, ESCMID, and IDSA or BTS clinical practice guidelines.1, 2, 4

With the exception of M malmoense, where recommendations are based on two randomised controlled trials and three retrospective cohort studies, the consensus recommendations by the panel members for the other six NTM species are based on case reports and case series only, thus are graded to be very low level evidence. Higher level evidence from patient registries and clinical trials to determine the best treatments for patients affected by pulmonary diseases caused by the other six NTM species are needed to inform clinicians in the future about the best management options for their patients.

This online publication has been corrected. The corrected version first appeared at thelancet.com/infection on February 3, 2022

Contributors

CL, CLD, and EC developed the idea and outline for the manuscript. SLK performed the electronic systematic literature searches. All co-authors contributed equally to the hand-search of the selected literature, the consensus process, drafting of the manuscript, and manuscript revision.

Declaration of interests

CLD reports grants and personal fees from Insmed, Paratek, and Spero; personal fees from AN2 and Matinas, and grants from BugWorks; outside the submitted work. DEB reports grants and personal fees from Insmed. CL is supported by the German Center for Infection Research (DZIF) and reports personal fees from Chiesi, Gilead, Janssen, Novartis, Oxfordimmunotec, and Insmed outside the submitted work. TKM reports grants and personal fees from Insmed; and personal fees from Astra Zeneca, RedHill Biopharma, Novartis, and Spero; outside the submitted work. KNO is supported by the intramural research program of the NHLBI, NIH and reports grants from Beyond Air outside the submitted work. KW reports grants and personal fees from Insmed; and personal fees from Paratek, Red Hill Biopharma, Horizon, and Spero; outside the submitted work. All other authors declare no competing interests.

Acknowledgments

CL is supported by the German Center for Infection Research (DZIF). KNO is supported by the intramural research program of The National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH).

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