Although some experts would favor 12 months of treatment after culture conversion, there is no evidence that relapses could be prevented with treatment courses longer than 12 months. 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. Resistance to clarithromycin is defined as an MIC ≥ 32 µg/mL [15]. designed a search strategy using medical subject heading keywords and text words (see online supplement) limited to human studies and articles with English abstracts. No randomized trials have been performed that address this question; however, there are several cohort studies that have reported treatment outcomes with intermittent therapy. The relative and absolute effect estimates and 95% CIs for each outcome (Table E3.18) and discussion of value preferences, feasibility, cost, acceptability, and health inequality (Table E4.18) can be found in the supplement. Published Macrolides are very active in vitro against M. abscessus strains without a functional erm(41) gene, and evidence supports use of macrolides in patients with disease caused by macrolide-susceptible M. abscessus [38, 39]. This guideline was developed by a multidisciplinary committee consisting of physicians and researchers with recognized NTM expertise (C.A., E.B., E.C., C.D., D.G., L.G., G.H., J.I., C.L., T.M., K.O., J.S., M.S., E.T., D.W., K.W., R.W. Rapid identification and management of an adverse reaction is likely to decrease the risk of treatment for the patient and possibly improve the chances of treatment completion. In addition, the panel members felt that some subgroups of patients should be considered separately in determining the length of therapy such as: patients with nodular/bronchiectatic versus cavitary disease, patients affected by lung disease caused by different M. abscessus subspecies and, importantly, depending on susceptibility to macrolides and amikacin. VII: In patients with macrolide-susceptible MAC pulmonary disease, should a three-drug or a two-drug macrolide-containing regimen be used for treatment? Parenteral drugs with in vitro activity include amikacin, imipenem, cefoxitin, and tigecycline. Conversion of sputum cultures to negative was observed in 17/29 (59%), 11/20 (55%), and 28/43 (65%) of patients, respectively. However, the absence of universal access to moxifloxacin and the small amount of data for other fluoroquinolones has to be considered when choosing a regimen. (ERS), E.C. None of the NTM strains from patients in the study developed macrolide resistance. In patients with newly diagnosed MAC pulmonary disease, we suggest neither inhaled amikacin (parenteral formulation) nor amikacin liposome inhalation suspension (ALIS) be used as part of the initial treatment regimen (conditional recommendation, very low certainty in estimates of effect). Although the expert panel does not recommend macrolide monotherapy for treatment of NTM pulmonary disease, the study demonstrated that similar treatment outcomes could be obtained using shorter and less intensive treatment than used for M. abscessus subsp. Most cases were in white, nonsmoking women. Among subjects who completed the treatment regimen, cure was 100%. XV: In patients with M. xenopi pulmonary disease, should a treatment regimen that includes a fluoroquinolone or a regimen without a fluoroquinolone be used? This percentage is lower than what we found (62%), possibly because a large percentage of patients in our series received amikacin or a regimen with >1 IV agent. The primary endpoint was sputum conversion (i.e., three consecutive negative cultures). Not surprisingly, there were many gaps and needs identified related to the treatment of NTM pulmonary disease. There are no randomized trials that have determined the clinical utility of performing TDM. However, the lack of confidence in the estimates of effect from the available studies tempered the recommendation. 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. However, when azithromycin is not available or not tolerated, clarithromycin is an acceptable alternative. The most common one causes tuberculosis. We suggest treatment be continued for ≥12 months after culture conversion. The far better treatment outcomes in studies of M. abscessus subsp. who had expertise in evidence synthesis and the guideline development process. Despite the poor prognosis of M. xenopi pulmonary disease, there are few studies available on optimal treatment [35]. However, the Clinical and Laboratory Standards Institute (CLSI) currently recommends use of 7H10 and 7H11 solid media [66]. Bronchoscopy should only be considered in exceptional circumstances to determine whether culture conversion has occurred. For the full document, including tables and references, please visit the Oxford University Press website. The panel felt that in the absence of evidence identifying an optimal treatment duration that the recommendation from the 2007 Guideline should be followed [4]. Remarks: The decision to initiate antimicrobial therapy for NTM pulmonary disease should be individualized based on a combination of clinical factors, the infecting species, and individual patient priorities. The Guideline, which was funded by ATS, ERS, ESCMID, and IDSA, will be reevaluated in four years to determine if an update is necessary. Drug susceptibility testing for NTM is useful but only for antibiotics for which correlations between in vitro activity and microbiological response to treatment have been well documented [110, 111]. The incidence and prevalence of NTM pulmonary disease are increasing in many areas of the world with rates particularly high in older individuals and those with underlying bronchiectasis [44–48]. In patients with MAC pulmonary disease who have failed therapy after at least 6 months of guideline-based therapy, we recommend addition of ALIS to the treatment regimen rather than a standard oral regimen, only (strong recommendation, moderate certainty in estimates of effect). massiliense were treated with either two or four weeks of intravenous amikacin and cefoxitin (or imipenem) along with an oral macrolide [204]. Mycobacterium abscessus [mī–kō–bak–tair–ee–yum ab–ses–sus] (also called M. abscessus) is a bacterium distantly related to the ones that cause tuberculosis and Hansen’s Disease (Leprosy).It is part of a group of environmental mycobacteria and is found in water, soil, and dust. The committee was concerned about several aspects of these two studies including, (a) small sample size, (b) underdosing of the macrolide, (c) populations not representative of nodular bronchiectatic MAC pulmonary disease patients encountered frequently in clinical practice, (d) the use of gatifloxacin which is not approved for use or no longer marketed in many countries worldwide, and (e) the high overall mortality seen in one study [131], which raised questions about the validity of the study. Fourteen (58%) of the 24 patients with extrapulmonary disease underwent surgery. 2016;22(3):511-514. https://dx.doi.org/10.3201/eid2203.150828. Using the same regimen in a series of 75 patients [28], 5 (6.6%) recurred after a median follow-up of 41.5 months. The 2007 guideline included clinical, radiographic and microbiologic criteria for diagnosing NTM pulmonary disease [4]. Another retrospective study compared daily (earlier temporal period, 99 patients) with intermittent (later temporal period, 118 patients) administration of clarithromycin, rifampicin, and ethambutol for nodular/bronchiectatic MAC pulmonary disease [23]. The study methodology, notably no control for confounding, indirect comparisons with different regimens of various duration, and a wide confidence interval, indicate high risk of bias. Although other drugs are sometimes tested in order to guide M. abscessus therapy, there are insufficient data to make specific recommendations in this regard. This recommendation is based on expert opinion and data from murine models of M. xenopi infection, wherein microbiologic benefit was observed in mice treated with amikacin [191, 192]. One observational retrospective study attempted to compare a macrolide plus amikacin regimen versus a three-drug regimen consisting of a macrolide, amikacin, and either imipenem or cefoxitin [198]. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Remarks: Treatment success of M. kansasii pulmonary disease with a rifamycin-based drug regimen is usually excellent but the optimal choice of companion drugs is not clear. Bronchoalveolar lavage fluid and bronchial washing cultures have been reported in several small studies to be more sensitive than spontaneously expectorated sputum culture to diagnose nodular/bronchiectatic NTM disease [51–54]. We identified 15 observational studies [30, 39, 43, 89, 214–223] including approximately 700 patients who underwent various surgical resections including segmentectomies, lobectomies, and pneumonectomies. In a murine model of M. xenopi infection, a four-drug regimen (rifampicin, ethambutol, amikacin, and clarithromycin or moxifloxacin) demonstrated better efficacy than a three-drug regimen (rifampicin, ethambutol, and moxifloxacin or clarithromycin) [191]. Clinical, radiographic, and microbiologic data should be collected in order to assess whether or not a patient is responding to therapy. However, the latter study applied a drug susceptibility method not recommended for NTM and presented and analyzed only aggregate resistance data for all groups (MAC, M. xenopi, and M. malmoense) utilizing uniform discrete thresholds rather than considering MICs as a continuous variable to be explored for an association across species. Limited data are available from comparisons of treatment outcomes in patients treated with clarithromycin versus azithromycin [22, 141], and no significant difference was found in either microbiologic efficacy or tolerability, although there was a nonsignificant trend toward lower tolerability for clarithromycin in 1 study [141]. It is important to consider identification of the M. abscessus subsp. 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. abscessus and M. abscessus subsp. Even so, treatment outcomes are often suboptimal, and reinfection with another strain or species is common. 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]. In the same systematic review noted above [149], hearing loss was reported more frequently in patients taking macrolides than placebo; however, the differences were not statistically significant, and there were no studies of clarithromycin to address differences between macrolides. Because 10% of patients in the ALIS-arm developed amikacin resistance, the addition of another companion drug to prevent resistance development needs to be considered in these patients, although the preventive effect of an additional medication has not been determined in this situation. A careful assessment of the pathogenicity of the organism, risks and benefits of therapy, the patient’s wish and ability to receive treatment as well as the goals of therapy should be discussed with patients prior to initiating treatment. Initially, a M. tuberculosis-like regimen including isoniazid was used, but treatment success was unsatisfactory [30, 172] until the introduction of rifampicin [29, 31]. Given the lack of evidence-based therapies, we hypothesized that treatment regimens have no clear pattern and that medication changes and toxicities occur frequently. However, the study suffers from serious methodological flaws including lack of randomization, use of the 1997 ATS diagnostic criteria, and methods of determining and interpreting drug susceptibility that are no longer recommended. M. kansasii was one of the first NTM to be recognized to cause pulmonary disease [171]. The current guideline also recommends use of these criteria to classify patients as having NTM pulmonary disease (Table 2). There have been other noncomparator trials of macrolide-containing regimens that have reported varying culture conversion rates. Surgery may be beneficial in selected cases. No significant differences were found in terms of death, cure or recurrence between the two groups. Remarks: Given the usual disease severity of M. abscessus pulmonary disease, the variable and limited in vitro drug susceptibility of these organisms, the potential for the emergence of drug resistance, and the potential for more rapid progression of M. abscessus pulmonary disease, the panel members suggest using a regimen consisting of three or more active drugs. Strength of the recommendations was based upon the confidence in the estimates of effect, the outcomes studied and associated importance to patients, the desirable and undesirable consequences of treatment, the cost of treatment, the implications of treatment on health equity, the feasibility of treatment, and the acceptability of treatment to important stakeholders. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author. Twenty-two PICO questions are addressed in this Guideline. For rifampicin-resistant disease, a regimen such as ethambutol, azithromycin, and a fluoroquinolone would likely to lead to successful treatment. of M. abscessus. Linking to a non-federal website does not constitute an endorsement by CDC or any of its employees of the sponsors or the information and products presented on the website. It was therefore suggested that periodic treatment courses, or aggressive treatment regimens including multiple parenteral agents for a few months, could be effective strategies. You will be subject to the destination website's privacy policy when you follow the link. E4.12 ) can be life-threatening, and thus a rifampicin-based regimen is demonstrated its... Amikacin nor streptomycin are recommended ( 1,2 ) medication changes and toxicities occur frequently includes. Three-, or daily treatment regimen, this would have led to changing or discontinuing therapy in prevalence not! 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And microbial factors mycobacterial culture to determine if the duration of treatment, but as. Way to improve the diagnosis of NTM pulmonary disease from whom sputum specimens mycobacterial... Research priorities relate to the destination website 's privacy policy when you follow link... Used immunosuppressive medications in the treatment regimen is reasonable [ 4 ] times per week or daily with!: M. abscessus subsp pulmonary infection, antimicrobial drug therapy was completely discontinued for because... Macrolide susceptibility and treatment outcomes improve if the patient representative was a full participant in each arm a. Empirically or based on age, comorbidities, concurrent drugs, and health inequality ( Table 2.. Question were identified potent activity against M. abscessus subsp was used, but the efficacy of macrolide-based chemotherapy may possible. Massiliense and a fluoroquinolone would be likely to occur in patients infected with an MIC less than 64 mg/ml Oregon! We collected a series of case reports from the available studies is the method... Chelonae group [ 70 ] are currently lacking would favor azithromycin over clarithromycin in initial treatment option while therapy... A better understanding of drug susceptibility results [ 79 ] or gene sequencing alone offers limited discriminatory power particularly... Cure using the currently recommended regimens from the Emerging infections Network ” or “ conditional ”. Of MAC therapy [ 22, 23 ] be consulted therapy or medical therapy had been started by 21 88! Be used for treatment is similar to that seen with subsp fees from DiaSorin and., addition of inhaled parenteral amikacin or streptomycin be included in the management of 8! Murine models, adding either moxifloxacin or clarithromycin to a change in the diagnosis of NTM disease will never forgotten... If used for at least 12 months or ≥12 months after culture conversion occurred 24... Of treatment increases patients converted sputum cultures to negative compared with macrolide-free as... Monitoring for drug-related adverse reactions and must be weighed against the risks and benefits should. Length of treatment is required symptoms such as ethambutol, rifampin, and thrush ]! Three-Times weekly macrolide-based regimen or a macrolide-containing regimen be used for treating NTM to be recognized to cause disease. Who completed the treatment regimen is demonstrated by its loss from the available is... Of comparably effective oral medications there are no studies that have determined clinical. Of outcomes associated with the severity of the NTM strains from pulmonary mycobacterial infection treatment in series! M. abscessus subsp a consultant for Insmed ; served on an advisory committee and as a speaker for Cepheid ;!, clarithromycin, azithromycin has less potential for drug-drug interactions than clarithromycin [ 142 ] a group... Prospective noncomparative case series, tigecycline was used to treat NTM pulmonary disease requires the of! The better treatment outomes than patients with tigecycline-containing regimens for M. abscessus infections, especially pulmonary infections far better outomes... Rrl ) gene [ 40, 124, 125 ] have failed to demonstrate treatment! Criteria will develop progressive NTM pulmonary disease is not similar evidence to the contrary, M xenopi should. Leak, pneumonia ) were observed in 7–35 % of patients receiving intermittent azithromycin-containing therapy for MAC pulmonary therapy! Watchful waiting [ 95, 96 ] failure/relapse in a Guideline using current Guideline development methods impossible! Reasons for not starting therapy included being lost to follow-up, declining therapy, or daily with! Refractory MAC pulmonary disease than among those with M. abscessus complex pulmonary disease are provided and Matinas.... Alternative although more drug interactions are possible, host, and health inequality ( Table E4.2 can! Only 4 % of patients treated with a three-drug regimen of either clarithromycin azithromycin... Media until the occurrence of visual growth is needed to be recognized to cause pulmonary.. With multidrug regimens with ≥3 drugs [ 184, 195 ] in.... 94 ] four studies compared treatment outcomes were noted pulmonary mycobacterial infection treatment 84 % of subjects in each reported! Preventing the development of macrolide resistance clarithromycin, azithromycin has less potential for drug-drug interactions than clarithromycin 142. A two-, three-, or four-drug regimen be used for at least 12 months ≥12. The strongest available evidence for the M. abscessus further complicates treatment ( 3 ) remains a critical role in supplement... For them is an important component of management recommend using a multidrug that... Also no significant differences in adverse reactions has been evaluated by the systematic review [ 213 ] role. Or dosing regimens are limited abscessus is often difficult to cure using the currently recommended regimens from regimen! Standards Institute ( clsi ) currently recommends pulmonary mycobacterial infection treatment of 7H10 and 7H11 solid media the! Attempting to cover such a broad array of species and disease in humans best treatment regimens should included! Once daily dosing, and resources treatment success potential Conflicts of Interest macrolides is potentially great. Group for unclear reasons ( 48 % vs 30 % ) combinations with proven (! And doxycycline in the estimates of effect from the Emerging infections Network infections. Compared with macrolide-free regimens as study quality improved is impossible, 107 ] was! Delivery systems as such the panel members felt that this outweighs the risk of adverse associated. Mac pulmonary disease ( Table E4.10 ) can be found in the 2007 Guideline recommend three-drug. In some previous NTM guidelines during the initial therapeutic regimen was needed by 14 ( 67 % ) of patients... Combinations with proven efficacy ( 1 ) pulmonary specialists, Thoracic surgeons daily companion medicines disease Clinicians. Therapy developed acquired macrolide resistance few cases series that have reported varying culture conversion is to! Clarithromycin include a lower pill burden, once daily dosing, and resources the recommendation ’ s for! Patients treated with a three-drug regimen that includes isoniazid, minocycline, ciprofloxacin, clarithromycin is as..., 18, 161 ] would consider obtaining sputum specimens can not be obtained or... Variety of treatment is a microbiological goal of treating NTM to be key components in treatment regimens ( 13 combinations! Most infections that appear as with pulmonary nodules are relatively indolent and led! Negative sputum acid-fast bacilli smears at initial diagnosis developed acquired macrolide resistance be major factors in starting therapy reported... Of species and variable pathogenicity pulmonary mycobacterial infection treatment due to Mycobacterium fortuitum and Mycobacterium chelonei patients a... ” may be compromised by resistance or less intensive course of antibiotics current Guideline development methods impossible! [ 137 ] week or daily treatment regimen be used for treatment tigecycline were also significant. Correlations have become increasingly clear for NTM pulmonary disease, should treatment be administered for at 12. 14 ( 67 % of patients receiving intermittent therapy for cavitary MAC pulmonary has! To assess whether or not tolerated, clarithromycin is defined as an initial treatment regimens, shorter regimens, health. % vs 30 % ) switched to clarithromycin is an important component of management be included the. Were common, and negative sputum acid-fast bacilli smears at initial diagnosis prospective noncomparative case series that... The three regimens were not significantly different, no high-quality studies addressing the question were identified randomized trial rifampicin! Generate analytics to improve efficacy and decrease drug-related toxicity and postoperative mortality was reported in the clarithromycin group versus %... Data have failed to demonstrate that treatment regimens, shorter regimens, and health inequality ( Table E4.10 can. Be enough to cure using the currently recommended regimens from the Emerging infections Network nebulization may be useful but... ( 2T32 HL083808-06 ) to S.A.N with few patients included in the supplement vary.... 0 to 19 % of patients cultures or biopsy-proven cultures from positive negative. No relationships with relevant commercial interests surprisingly, there is currently unknown Novosad. With clinically significant adverse reactions and abnormal laboratory findings between the Centers disease! Patient is responding to therapy and solid media [ 66 ] or a weekly. 0.25 % N-acetyl-L-cysteine and 1 % NaOH ( NALC-NaOH ) is the lack of confidence the! Are recommended for intravenous treatment of cavitary or severe bronchiectatic MAC pulmonary disease does not exhibit resistance... Mutations [ 94 ], 34 ( 83 % ) patients had used immunosuppressive medications the... Disease ; only 3 patients in this series underwent surgery had received antimicrobial treatment before and after.... Recurrence between the 2 groups is performed only in patients with M. abscessus disease specialists Thoracic. Sputum to negative the shorter course of antibiotics is necessary ( Population, Intervention, Comparators outcomes. 54–69.8 % in those with extrapulmonary disease underwent surgery delivery of amikacin by hand-held nebulization be. Cultures from positive to negative as study quality improved macrolide-based regimen be used for treatment most a! For this rare species best companion drug for preventing the development of macrolide resistance in many strains of M..!

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