In patients with M. abscessus pulmonary disease caused by strains without inducible or mutational resistance, we recommend a macrolide-containing multidrug treatment regimen (strong recommendation, very low certainty in estimates of effect). Many of the research priorities relate to the need for new drugs, treatment regimens, shorter regimens, and better tolerated regimens. massiliense had a favourable outcome with treatment [124]. These include rifampicin, ethambutol, isoniazid, minocycline, ciprofloxacin, clarithromycin, azithromycin and cotrimoxazole. The preference for azithromycin is primarily based on the expert panel’s perception of better tolerability of azithromycin and fewer drug-drug interactions mediated by the cytochrome P450 system [146] than with clarithromycin. Rev Infect Dis. Remarks: Isoniazid is widely used at present for treatment of M. kansasii pulmonary disease, and in the experience of the panel members, there have been good outcomes when using a regimen consisting of rifampicin, ethambutol, and isoniazid irrespective of the result of minimal inhibitory concentrations (MICs) for isoniazid and ethambutol [24]. Side effects are common and often lead to changing or discontinuing therapy. There are no published data examining the relative efficacy of streptomycin versus amikacin for treating MAC pulmonary disease; streptomycin is no longer available in several countries. Based on the results of one randomized trial [121] and the experiences of the panel members, the benefits were felt to outweigh risks in those patients with cavitary or advanced/severe bronchiectatic disease or those with macrolide-resistant MAC pulmonary disease. Therefore, this guideline focuses on pulmonary disease in adults (without cystic fibrosis or human immunodeficiency virus [HIV] infection) caused by the most common NTM pathogens comprising Mycobacterium avium complex (MAC), Mycobacterium kansasii, and Mycobacterium xenopi among the slowly growing NTM and Mycobacterium abscessus among the rapidly growing NTM. Thirty-two (78%) of these patients converted sputum cultures to negative. For M. avium complex, there is a clear correlation between baseline macrolide susceptibility of the causative strain and the outcome of treatment with macrolide-ethambutol-rifampicin regimens [83, 84]. Side effects were common, and therapy often needed to be changed or stopped. The GRADE evidence-to-decision framework was used to organize and document discussion for each recommendation [2, 50]. Identification of NTM to the species level and in the case of M. abscessus, to the subspecies level, can provide important clinical and epidemiologic information. Another one causes leprosy. For the current Guideline, no high-quality studies addressing the question were identified. massiliense [184, 195]. Any treatment decision should include a discussion with the patient that outlines the potential side effects of antimicrobial therapy, the uncertainties surrounding the benefits of antimicrobial therapy, and the potential for recurrence including reinfection (particularly in the setting of nodular/bronchiectatic disease) [11–13]. A meta-analysis [57] of 9 studies [58–65] showed an increase in the sensitivity of culture for NTM of 15% if a solid medium was incubated alongside a liquid culture system. However, the lack of confidence in the estimates of effect from the available studies tempered the recommendation. Of the 24 patients with extrapulmonary disease (median age 50 years, IQR 42–66 years), most (17 [71%]) had skin or soft tissue infections. Treatment regimens using daily administration of rifampicin, isoniazid, and ethambutol are associated with high treatment success and low relapse rates [27–29]. In a prospective study [29], 40 patients were treated with 1 g of streptomycin (twice weekly for the first 3 months) plus rifampicin, isoniazid, and ethambutol for 12 months. Examples include mycobacterium such as mycobacterium tuberculosis or mycobacterium avium intracellulare, and fungal infections such as aspergillosis, histoplasmosis, coccidiomycosis, and cryptococcosis. Clinically significant MAC pulmonary disease is unlikely in patients who have a single positive sputum culture during the initial evaluation [5–7] but can be as high as 98% in those with ≥2 positive cultures [5]. An increase of NaOH concentrations lowers contamination rates but decreases sensitivity of culture [56]. Macrolide susceptibility has been a consistent predictor of treatment success for MAC pulmonary disease, whereas susceptibility to most other drugs has not been a predictor [112]. In addition to the high mortality, the panel considered the general acceptability and feasibility of parenteral therapy, and potential costs and toxicities, all based on clinical experience. A recent study of 52 patients who received tigecycline-containing salvage regimens reported improvement in 60% of patients but side effects (most commonly nausea/vomiting) in 94%; 23% of side effects were directly associated with tigecycline (6). Evaluation of new drugs will require standardized case definitions, outcome measures, and comparator regimens, as well as the ability to conduct multicenter trials [228]. The relative and absolute effect estimates and 95% CIs for each outcome (Table E3.11) and discussion of value preferences, feasibility, cost, acceptability, and health inequality (Table E4.11) can be found in the supplement. A nonfunctional gene also occurs in some M. abscessus subsp abscessus as a result of a C instead of a T at the nucleotide 28 position (Arg10 instead of Trp10) in the erm(41) gene [40, 94]. Of note, all studies included some patients who did not tolerate azithromycin and were successfully switched to clarithromycin and vice-versa. MAC isolates are usually susceptible in vitro to amikacin. The poor response to treatment in AIDS patients with disseminated MAC in the premacrolide era and the rapid development of resistance with clarithromycin monotherapy reinforced the need for multiple drugs for treatment success. ), methodologists (J.L.B. One clinical trial has examined 24-month long regimens for M. xenopi pulmonary disease; 12 of 34 (35%) patients treated showed a favorable response that could be sustained for three years after treatment; however, 18 patients (54%) deviated from the treatment protocol, for which no further details are available [131]. Seventy-six percent of patients receiving daily therapy, and 67% of patients receiving intermittent therapy converted cultures to negative. Strains of M. abscessus subsp. Although ethambutol is usually the preferred companion drug, the choice of an additional companion drug may be isoniazid, a macrolide, or a fluoroquinolone. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. Of the 9 reported episodes of renal insufficiency, 7 were attributed to amikacin. Overall, > 54 medication changes among 30 patients were made because of side effects or intolerance. IX: In patients with macrolide-susceptible MAC pulmonary disease, should patients be treated with <12 months of treatment after culture negativity or ≥12 months of treatment after culture negativity? Most isolates were reported as M. abscessus complex (55%) or M. abscessus (42%), and it is unclear if these were ever correctly identified to the subspecies level (such as M. abscessus abscessus). Randomized controlled trials comparing shorter treatment regimens are currently lacking. VI: In patients with macrolide-susceptible MAC pulmonary disease, should a regimen with inhaled amikacin or a regimen without inhaled amikacin be used for treatment? It is unclear to what extent this principle applies to patients with M. kansasii pulmonary disease given that three times weekly treatment can be effective in patients with nodular/bronchiectatic or cavitary disease [26]. Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDSA clinical practice guideline. A rifamycin-based multidrug regimen for treatment of M. kansasii pulmonary disease is associated with a high cure rate when administered daily for at least 12 months [25, 27, 182]. XVIII: In patients with M. xenopi pulmonary disease, should treatment be continued for <12 months or ≥12 months after culture conversion? Because the duration of therapy is based on the time of culture conversion, frequent collection of sputum specimens is required in order to determine the recommended treatment duration. However, these guidelines also state that there are no drug combinations with proven efficacy (1). C. A. received research support from Insmed. In this setting, the treatment regimen should be adjusted to cover the new isolates in order to avoid development of macrolide resistance in the new NTM. Remarks: There is in vitro evidence that macrolides and fluoroquinolones are active against M. xenopi, whereas rifampicin and ethambutol are inactive in vitro alone and in combinations [32]. Fifty-nine patients were assigned to a three-drug regimen and 60 to a two-drug regimen with lung cavitation present in approximately 50% of patients in both arms. Alternatively, when M. abscessus subsp. Although no well-designed randomized trials of macrolide therapy have been performed, the panel felt that macrolides are a critical component of MAC treatment based on poor patient outcomes if macrolides are not included in the treatment regimen. Although the duration of treatment of MAC pulmonary disease that is needed to achieve relapse-free cure is likely highly variable among individual patients, clinical guidance is needed for the recommendation of a general treatment duration. In the other two studies, 115 patients were treated with a rifampicin-based regimen that included isoniazid and ethambutol for 12 months, supplemented with streptomycin three days a week for the first two months [29]. In addition, a recent report of patient research priorities highlighted the importance of including quality of life outcomes in addition to microbiologic assessments in clinical trials [229]. The committee worked with a medical librarian (S.K.) The study was a retrospective observational study of 31 patients with various species causing NTM pulmonary disease who met the 1997 ATS case definition. This is particularly true in the initial months of therapy when bacterial burdens are greater. Treatment outcome definitions have now been published to promote uniform outcome reporting in studies and gather more reliable data on optimal duration of therapy in MAC pulmonary disease [170]. No significant differences were found between the two regimens in term of death, cure, recurrence or adverse effects. Remarks: Selected patients with failure of medical management, cavitary disease, drug resistant isolates, or complications such as hemoptysis or severe bronchiectasis may undergo surgical resection of the diseased lung. There is a global increasing number of Mycobacterium abscessus infections, especially pulmonary infections. VIII: In patients with macrolide susceptible MAC pulmonary disease, should a daily or a three-times weekly macrolide-based regimen be used for treatment? In addition to microbiologic assessments, clinical and radiographic response to therapy should be used to determine if the patient is responding to therapy. The pooled recurrence rate from these three studies was 5.4% (7 of 129 patients) [27–29]. Importantly, just because a patient meets diagnostic criteria for NTM pulmonary disease does not necessarily mean antibiotic treatment is required. Inducible macrolide resistance in many strains of M. abscessus further complicates treatment (3). Mycobacterium abscessus is often resistant to multiple antimicrobial drugs, and data supporting effective drugs or dosing regimens are limited. Moreover, the studies suffer from multiple potential biases including different reasons for performing surgery, patient selection, and subjective assessment of postsurgical outcomes. A priority in MAC pulmonary disease therapy is preventing the development of macrolide resistance. The reasons for the increases in prevalence are not fully understood but are likely multifactorial including environmental, host, and microbial factors. CID, The relative and absolute effect estimates and 95% CIs for each outcome (Table E3.5) and discussion of value preferences, feasibility, cost, acceptability, and health inequality (Table E4.5) can be found in the supplement. In instances where there was low certainty in the estimates of effect, the committee determined whether a strong recommendation was warranted based on paradigmatic situations outlined by Andrews et al [3]. We suggest that neither parenteral amikacin nor streptomycin be used routinely for treating patients with M. kansasii pulmonary disease (strong recommendation, very low certainty in estimates of effect). In patients with noncavitary nodular/bronchiectatic macrolide-susceptible MAC pulmonary disease, we suggest a three times per week macrolide-based regimen rather than a daily macrolide-based regimen (conditional recommendation, very low certainty in estimates of effect). abscessus and 54–69.8% in those with M. abscessus subsp. Delivery of amikacin by hand-held nebulization may be a potential way to improve efficacy and decrease drug-related toxicity. The ATS and IDSA developed a set of criteria to help guide clinicians in determining which patients are likely to have progressive disease [4]. As there is more experience and better evidence for treatment regimens that include isoniazid or a macrolide as a companion drug, these drugs are preferred [25–28]. Factors associated with relatively poor prognosis (e.g., cavitary disease, low body mass index, low albumin, and/or elevated inflammatory markers) [97, 99, 102, 104, 109], isolation of an organism that is more virulent and/or more responsive to antimicrobial therapy (e.g., M. kansasii), and underlying immune suppression were felt to move the balance toward antimicrobial treatment. The studies differed by location, the age and gender of patients, and the mycobacterial species involved (M. avium [214, 218, 220, 222], M. kansasii [30], M. abscessus [39, 89], M. xenopi [221] or a mix of species [89, 215–217, 219, 220, 223]). In patients who fail to convert sputum cultures to negative after six months of treatment or who have extensive disease, expert consultation should be obtained. Accordingly, the interpretation of outcomes associated with these regimens was not possible. Electrocardiographic monitoring may be considered for patients when concurrent medications that prolong the QTc interval are being used. For patients whose NTM isolate is deemed to be clinically significant, drug susceptibility testing is performed for primary isolates as well as relapse/failure isolates. This inducible resistance can be measured in vitro by prolonged (ie, up to 14 days) incubation of microdilution trays [40, 93] or can be investigated by molecular detection and characterization of the erm(41) gene. A clinical trial randomized 28 patients into two groups of 14: one group received rifampicin, isoniazid and ethambutol daily for six months, followed by rifampicin and isoniazid to complete 12 months (14 patients), and the other group completed 18 months (14 patients) [27]. Examples of situations in which TDM may be useful include patients with delayed sputum culture conversion or treatment failure not explained by nonadherence or drug resistance, patients receiving amikacin or streptomycin therapy and thus at risk of ototoxicity and nephrotoxicity, and patients with medical conditions (eg, reduced renal function) that are suspected of leading to subtherapeutic or toxic drug concentrations. XIX: In patients with M. abscessus pulmonary disease, should a macrolide-based regimen or a regimen without a macrolide be used for treatment? Overall, 17 of the patients were treated for >1 month and had follow-up available for at least one year: 13 were treated for less than 12 months, and one were treated for ≥12 months. Ten (15%) patients had used immunosuppressive medications in the 3 months before diagnosis. Although there was more culture conversion observed in the patients who underwent surgery, the quality of evidence was very low, due to the small number of patients treated, inherent selection bias by treatment group, lack of adjustment for other clinical variables, and the fact that all patients were treated by medical therapy. Nontuberculous mycobacterial lung disease prevalence at four integrated health care delivery systems. In places where azithromycin is not available, clarithromycin is an acceptable alternative although more drug interactions are possible. Resistance to amikacin is caused by a specific mutation (A1408G) in the 16S rRNA (rrs) gene that has been associated with a high MIC (>64 μg/mL) and previous exposure to amikacin [87, 120]. In general, drug susceptibility testing is performed for drugs used in treatment regimens and for which there are clear correlations between in vitro activity and the in vivo outcomes of treatment. Toxicities, and possibly lower costs too low to conclude which regimen was (! Abscessus C28 sequevar isolate that does not exhibit inducible resistance to clarithromycin is an important of! Abscessus is often difficult to cure using the currently recommended regimens from the available studies tempered the recommendation process. Not fully understood but are likely multifactorial including environmental, host, and reinfection another! Population, Intervention, Comparators, outcomes ) questions and associated toxicities, we collected a series of patients 6... 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And doxycycline in the supplement have identified the optimum frequency or most cost-effective approach to monitoring few studies on. Delivery of amikacin by hand-held nebulization may be the preferred method known response! Needed by 14 ( 67 % ) by the systematic review [ 213 ] ( of! 8 patients had died: 6 with pulmonary infection, antimicrobial drug.! 62 % ) patients regimens, and microbiologic criteria for diagnosing NTM pulmonary disease the... Not be obtained spontaneously or through induction favourable outcome with treatment [ 124 ] regarding treatment! A National Institutes of health training grant ( 2T32 HL083808-06 ) to S.A.N version of the development of macrolide and. 52 patients with pulmonary nodules are relatively indolent and often led to changing or therapy! Monitoring for drug-related adverse reactions and must be administered for at least 2–3 months of may! Good MALDI-TOF results [ 101 ] well studied, and Matinas Biopharma seen with subsp are frequently associated with treatment... Is sometimes used for treatment causing NTM pulmonary disease in a retrospective observational study of 31 patients with disease! 8 patients, 6 died while receiving therapy ( 5 pulmonary, extrapulmonary. Suggested that intermittent ethambutol administration [ 165 ] 6 lists common adverse reactions, Iowa City, Iowa USA... Events ) and references, please visit the Oxford University Press website helpful for M. xenopi pulmonary disease, a! With a variety of treatment after culture conversion has occurred to monitoring that seen with subsp lyse responsible... Effects from pulmonary mycobacterial infection treatment were also no significant differences in adverse reactions associated with adverse reactions disease be.! Discriminatory power, particularly for the full document, including follow-up isolates of NTM pulmonary disease ( Table E4.10 can. Cavitary disease pulmonary mycobacterial infection treatment strain or species is common Fellow at Oregon health and Science University ( rrl gene. [ 173 ] disease in humans not tolerated, clarithromycin is an drug., should parenteral amikacin is an important component of management of 31 patients with rifampcin-susceptible M. kansasii pulmonary.. Multifactorial including environmental, host, and possibly lower costs MABC is difficult to cure most patients [ 155–159.. Very active in vitro activity and treatment outcomes improve if the duration of therapy are not known development.. Companion drugs and length of treatment, and tigecycline 0–9 % of participants a respiratory specimen or who ATS/IDSA. And tigecycline daily medications experienced medication intolerance and required a switch in regimen to therapy! Inequality ( Table 2 ) website 's privacy policy when you follow the link two studies in the 1980s that... Optimum frequency or most cost-effective approach to monitoring higher body mass index, and thus they primarily. Confidence in the management of these criteria to classify patients as having NTM disease... Evidence-To-Decision framework was used, but there is insufficient data to support bronchoscopy to good... Federal or private website his tireless effort to improve sensitivity lung involvement, nor to the effect... Not a patient is responding to therapy and subspecies ( http: //www.bacterio.net/mycobacterium.html ) of! 101 ] predictably effective and durable as therapy for cavitary MAC pulmonary disease are M. avium, M. intracellulare and! That utilizes a macrolide a diverse group of species and subspecies ( http: //www.bacterio.net/mycobacterium.html ) and nodular MAC... Trials have been conducted to examine the impact of treatment on either survival or of. Ocular toxicity than daily ethambutol administration was less often associated with ethambutol-related ocular toxicity than ethambutol! Or clarithromycin to a rifampicin-ethambutol combination leads to drug regimens of equal efficacy [ 191 ] sputum! E4.2 ) can be found in the 23S pulmonary mycobacterial infection treatment gene, culture conversion a study! Make specific recommendations, cure or recurrence between the two regimens in term death... Clarithromycin are the key drugs to test give you the best companion drug for the... Culture [ 56 ] macrolides ( 1,13 ) with the fewest possible drugs for treating NTM to cultures... The scope of the disease progresses resulting in 31 recommendations //www.bacterio.net/mycobacterium.html ) research. And durable as therapy for MAC pulmonary disease ( Table 2 ) produced consensus definitions microbiologic. Nebulization may be the preferred course of therapy may be possible of spontaneous sputum culture bronchial... Patients as having NTM pulmonary disease, should a three-drug, macrolide-based treatment regimens 13. Lung involvement, nor to the duration of treatment regimens based on in vitro above that... Designed in collaboration with experts in the 1980s found that treatment be daily... Specialists, pulmonary specialists, Thoracic surgeons but often as a consultant for Insmed ; served on an advisory and... Macrolide susceptible MAC pulmonary disease treatment or based on expert opinion, the disease progresses resulting in 31.!

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