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TEAEs reported in ≥10% of patients in the ALIS+GBT arm included dysphonia, cough, hemoptysis, dyspnea, fatigue, diarrhea, nausea, and oropharyngeal pain. Twenty-two PICO questions are addressed in this Guideline resulting in 31 recommendations. Streptomycin was used in early noncomparative treatment trials during the initial months of treatment for both cavitary and nodular/bronchiectatic MAC pulmonary disease [83, 138]. Like in other NTM infections, a multidrug therapy is used to avoid selecting for drug resistance, but the optimal number and combination of drugs are not known. Reduced therapeutic options exist against this opportunistic pathogen due to its high intrinsic and acquired levels of antibiotic resistance. Two additional retrospective studies have suggested that the inclusion of a parenteral aminoglycoside administered for ≥6 months in addition to adjunctive surgery improves outcome for patients with macrolide-resistant MAC pulmonary disease [16, 18]. Adverse reactions were very common in both treatment arms: treatment-emergent adverse events (TEAE) were reported in 98.2% and 91.1% of patients in the ALIS+GBT and GBT-alone arms, respectively. Lancet Infect Dis. One additional observational retrospective study suggested that multidrug therapy is associated with improved quality of life in M. abscessus patients, but this study did not compare outcomes according to different drug regimens [108]. However, they did not distinguish patients with M. abscessus isolates with and without functional erm genes. Some experts would use intermittent courses of multidrug therapy instead of transitioning to a longer continuation phase, although almost all published studies treated patients for >12 months. Previous guidelines recommend using a multidrug regimen including ≥2 of these antibiotics to which the organism is susceptible in vitro. This observational, retrospective study included 30 patients with M. abscessus pulmonary disease who met the diagnostic criteria defined in the 2007 Guideline. Ten (15%) patients had used immunosuppressive medications in the 3 months before diagnosis. A panel of experts was carefully selected and screened for conflicts of interest and included specialists in pulmonary medicine, infectious diseases and clinical microbiology, laboratory medicine, and patient advocacy. In patients with M. xenopi pulmonary disease, we suggest that treatment be continued for at least 12 months beyond culture conversion (conditional recommendation, very low certainty in estimates of effect). 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]. No significant difference was found in the cure rate between the two groups. Unfortunately, the predictive values of these criteria are not well studied, and thus they serve primarily as a guide to clinicians. For the remainder, subculture on solid media until the occurrence of visual growth is needed to obtain good MALDI-TOF results [79]. However, systemic use of parenteral amikacin has been associated with a high frequency of renal, auditory, and vestibular toxicity [154]. In addition to microbiologic assessments, clinical and radiographic response to therapy should be used to determine if the patient is responding to therapy. Similarly, there are no data to support the use of isoniazid on a three times weekly basis in patients with M. kansasii pulmonary disease. Not surprisingly, there were many gaps and needs identified related to the treatment of NTM pulmonary disease. Any treatment decision should include a discussion with the patient that outlines the potential adverse 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]. 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? Among the over 200 patients included in the studies, culture conversion ranged between 25–42% and 50–96% among those with subsp. Moreover, in this study that also included patients with M. avium or M. malmoense, adverse events were not reported separately for M. xenopi. Of the 9 reported episodes of renal insufficiency, 7 were attributed to amikacin. In this study, 34 patients were treated with either ciprofloxacin (n = 17) or clarithromycin (n = 17) in addition to rifampicin and ethambutol. Discussion of value preferences, feasibility, cost, acceptability, and health inequality (Table E4.17) can be found in the supplement. We suggest that treatment be administered for at least 12 months after culture conversion. Testing of other drugs may be useful, but there is insufficient data to make specific recommendations. In patients with M. xenopi pulmonary disease, we suggest a daily regimen that includes at least three drugs: rifampicin, ethambutol, and either a macrolide and/or a fluoroquinolone (e.g., moxifloxacin) (Tables 3 and 4). Our study had several limitations, including unknown specific subspecies of M. abscessus. Observational cohorts have noted wide variability in the proportion of patients with NTM pulmonary disease who are offered treatment (20–81%) likely contributing to selection bias [95, 98–105]. In patients with M. abscessus pulmonary disease, we suggest a multidrug regimen that includes at least three active drugs (guided by in vitro susceptibility) in the initial phase of treatment (conditional recommendation, very low certainty in estimates of effect). When the specific medication causing a side effect was known, it was most commonly amikacin (22 [30%]) or tigecycline (13 [18%]). The first study compared efficacy of a regimen containing rifampicin, ethambutol with or without isoniazid in 42 patients (20 vs 22) [36, 119]. Serious TEAEs were reported in 45 patients (20.2%) and 20 patients (17.9%) in the ALIS+GBT and GBT-alone arms, respectively. Although there is good in vitro activity of the fluoroquinolones against M. kansasii, no randomized clinical trial or case series have been published in which a fluoroquinolone was used for the treatment of M. kansasii pulmonary disease. Most common were nausea/vomiting (n = 17, 31%) and skin changes (n = 11, 20%) (Table 2). Mycobacterial infection or its reactivation is an anti-TNF therapy complication. ALIS is currently approved by the United States Federal Drug Administration for treatment of refractory MAC pulmonary disease. Only one study addressing this specific question was identified by the systematic review [213]. For the best chance of pulmonary disease cure, guidelines from the American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) recommend multidrug macrolide-based therapy based on susceptibility testing results and surgical resection. They’re harmless to most people. Of these 26.9% subsequently had MAC isolates with an MIC less than 64 mg/ml. Trials of monotherapy with clarithromycin, rifampicin, ethambutol, or clofazimine for HIV-associated disseminated MAC demonstrated that only clarithromycin susceptibility results correlated with treatment outcomes [113, 116]. Subsequent case series could not address the specific question but found that treatment duration of <6 months was associated with higher mortality and with recurrence [35]. Switching from one agent to the other is a strategy that may be considered in case of intolerance. The current guideline also recommends use of these criteria to classify patients as having NTM pulmonary disease (Table 2). Although other drugs are sometimes tested in order to guide M. abscessus therapy, there are insufficient data to make specific recommendations in this regard. 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]. Mycobacterium avium complex (MAC) is the major pathologic nontuberculous mycobacteria causing lung disease (LD) in humans worldwide. Although only 1 study was identified that attempted to evaluate the outcomes of treatment based on drug susceptibility results there are other studies that have correlated outcomes with in vitro activity. Of the 65 patients, 41 (63%) had pulmonary M. abscessus infection; 19 isolates were from bronchoalveolar lavage fluid and 16 from >2 sputum samples. Not all patients who have NTM isolated from a respiratory specimen or who meet ATS/IDSA diagnostic criteria will develop progressive NTM pulmonary disease. This strongly suggests that macrolides provide a very large benefit in the treatment of macrolide-suspectible M. abscessus. A three-drug regimen that includes isoniazid, rifampicin, and ethambutol was recommended in the 2007 Guideline [4]. 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. 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. Correct identification of NTM is important, as it can predict the clinical relevance of an isolate [8] as well as aid in the selection of a treatment regimen. Two studies described the association of serum concentrations of macrolides and treatment outcomes. Members of the M. abscessus Study Team: Lilian Abbo, Philip Brachman, Shingo Chihara, Daniel Gluckstein, K. V. Gopalakrishna, Donald R Graham, Alex Granok, R. Gordon Huth, Michael Klevay, James Leggett, Sarah Mooney, David Mushatt, Steven Norris, Lisa Oakley, Brian Petroelje, Hari Polenakovik, Susan Rhee, Kamla Sanasi-Bhola, Paul Southern, Mingquan Suksanong, Gregory Valainis, Mark Wallace, and Regina Won. A single study using standardized methods for quality of life assessment demonstrated improvement of quality of life associated with treatment of M. abscessus infection [108]. 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. In Croatia, six months of first-line antituberculosis treatment led to favorable outcomes in 10 of 20 patients (50%) [193]. Alternatively, when M. abscessus subsp. The pathogenicity of NTM species may differ between geographic areas [9, 10]. Only one randomized clinical trial has been published that compared ciprofloxacin with clarithromycin when added to rifampicin and ethambutol in patients with M. xenopi pulmonary disease [131]. This guideline focuses on pulmonary disease in adults (without cystic fibrosis or human immunodeficiency virus … R. J. W. served as the director of a university clinical laboratory that does NTM identification, molecular strain comparison, and susceptibility testing; received research support from Insmed as mycobacterial reference laboratory for a trial of the inhaled liposomal amikacin. In some instances, “watchful waiting” may be the preferred course of action. Listing a study does not mean it has been evaluated by the U.S. Federal Government. The 2007 Guideline expressed a preference for azithromycin over clarithromycin in initial treatment regimens [4]. Among patients with renal insufficiency attributed to amikacin, 71% were receiving it daily. 79 (2):74-84. . 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]. In all patients with M. kansasii pulmonary disease treated with an isoniazid, ethambutol, and rifampicin regimen, we suggest treatment be given daily instead of three times weekly (conditional recommendation, very low certainty in estimates of effect). Remarks: The panel felt that azithromycin was preferred over clarithromycin because of better tolerance, less drug-interactions, lower pill burden, single daily dosing, and equal efficacy. CLSI recommends that drug susceptibility testing be performed by broth microdilution [88]. Neither parenteral amikacin nor streptomycin are recommended for routine use in these patients. Nevertheless, the power is probably insufficient, with few patients included and few events occurred. Two studies in mice infected with M. xenopi have shown reduced colony forming units among mice treated with amikacin in addition to comparator regimens [191, 192]. Treatment regimens using daily administration of rifampicin, isoniazid, and ethambutol are associated with high treatment success and low relapse rates [27–29]. Similarly for extrapulmonary disease, macrolide-based treatment regimens based on susceptibility testing results are recommended (1,2). Diagnosis of NTM pulmonary disease requires the synthesis of clinical, radiographic, and microbiology data. abscessus or massiliense [38, 198, 199, 203, 206, 207]. Of note, all studies included some patients who did not tolerate azithromycin and were successfully switched to clarithromycin and vice-versa. A case series suggested that intermittent ethambutol administration was less often associated with ethambutol-related ocular toxicity than daily ethambutol administration [165]. Susceptibility testing panels for M. abscessus include at least amikacin, cefoxitin, imipenem, clarithromycin, linezolid, doxycycline, tigecycline, ciprofloxacin, and moxifloxacin. Clinical experience in 52 patients with tigecycline-containing regimens for salvage treatment of. Sputum culture conversion occurred in only 4% of patients with cavitary disease. Given the lack of data on the optimal duration of therapy, the panel voted unanimously to continue to follow the recommendations from the 2007 Guideline. 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]. Twenty-two PICO questions are addressed in this Guideline. 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]. Concurrent conditions included cystic fibrosis (n = 9, 14%), cancer (n = 7, 11%), and chronic obstructive pulmonary disease (n = 6, 9%). M. abscessus and its subspecies abscessus, bolletii, and massiliense are by far the most common causative agents of pulmonary disease due to rapidly growing mycobacteria. Novosad SA, Beekmann SE, Polgreen PM, et al. Resistance to clarithromycin is defined as an MIC ≥ 32 µg/mL [15]. massiliense were treated with either two or four weeks of intravenous amikacin and cefoxitin (or imipenem) along with an oral macrolide [204]. Preliminary data from a study in France in which randomized patients received either moxifloxacin or clarithromycin plus ethambutol and rifampicin reported no difference in the treatment success between the study arms [33]. Amikacin must be paired with adequate companion medications, such as a macrolide, ethambutol and possibly rifampicin and clofazimine, to prevent the emergence of acquired mutational resistance and predictable treatment failure [153]. Cookies are also used to generate analytics to improve this site as well as enable social media functionality. 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. 1981; 3 … There are two systematic reviews [184, 195] that have reported treatment outcomes in patients with M. abscessus pulmonary disease, but there are no studies that have directly compared the efficacy or safety of different multidrug regimens. 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. C. A. received research support from Insmed. The pathogenicity of NTM species may differ between geographic areas [9, 10]. Remarks: Regimens of three oral agents, rifampicin and ethambutol, and either isoniazid or a macrolide, achieve high rates of sustained culture conversion and treatment success in the treatment of M. kansasii pulmonary disease. A detailed review of the subject is beyond the scope of the Guideline but a brief review of clinically relevant laboratory issues is below. The significance of NTM isolated from the sputum of individuals who meet the clinical and radiographic criteria in Table 2 must be interpreted in the context of the number of positive cultures and specific species isolated. During the study, more patients in the ALIS+GBT arm had MAC isolates with postbaseline amikacin MIC > 64 μg/mL than those receiving GBT alone (10.3% vs 2.7%). , clinical and laboratory Standards Institute ( clsi ) currently recommends use of macrolides treatment! 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