記住我
ORIGINAL ARTICLE
Year : 2023 | Volume
: 12
| Issue : 1 | Page : 55-65
Nontuberculous mycobacteria isolation from sputum specimens: A retrospective analysis of 1061 cases
Aylin Babalik1, Emine Nur Ko1, Hamide Gl Sekerbey1, Gl Erdal Dnmez1, Ahmet Baliki1, Zeki Kiliaslan2
1 Department of Chest Disease, Istanbul Health Science University, Süreyyapaşa Chest Diseases and Thoracic Surgery Training and Research Hospital, Istanbul, Türkiye
2 Department of Chest Disease, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Türkiye
Correspondence Address:
Aylin Babalik
Istanbul Health Science University, Süreyyapasa Chest Diseases and Thoracic Surgery Training and Research Hospital, Istanbul
Türkiye
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/ijmy.ijmy_10_23
Background: In recent years, with the development of laboratory methods, the frequency of nontuberculosis mycobacteria (NTM) infections has increased. The primary aim of this study was to evaluate the clinical significance of therapeutic drug monitoring (TDM) growths in respiratory samples, and the secondary aim was to evaluate the treatment regimens and treatment outcomes of treatment for TDM disease. Methods: This study was a retrospective cohort study. Persons with NTM growth in respiratory samples admitted to the reference hospital between 2009 and 2020 were included in this study. Samples detected as NTM by the immunochromatographic rapid diagnostic test, those requested by the clinicians, species were determined by the hsp65PCRREA method. The subjects were classified into 3 groups: patients with NTM infection who received treatment (135, 12.7%), those followed up without treatment (690, 65.1%), and a last group of patients with Mycobacterium tuberculosis (TB) complex strains were isolated and received TB treatment (236, 22.2%). Initiating NTM treatment was decided in accordance with the American Thoracic Society recommendations. Results: The mean ± standard deviation age of patients was 53.8 ± 16.5 years, and 749 (70.6%) were male. In total, 278 (26.2%) out of 1061 cases had identified, and the most frequent species were MAC (81; Mycobacterium avium: 39, Mycobacterium intracellulare: 39, and MAC: 3), Mycobacterium abscessus (67), Mycobacterium kansasii (48), Mycobacterium fortuitum (23), Mycobacterium chelonae (12), Mycobacterium gordonae (11), and Mycobacterium szulgai (11). In the NTM treatment group, 116 (85.9%) of 135 patients had multiple culture positivity. Previous TB treatment history had 51 (37.8%) of 135 patients, respiratory comorbidities were evident in 37 (27.4%) of 135 patients. Thorax computed tomography imaging in 84 patients revealed nodule 38 (45.2%), consolidation 46 (54.8%), cavity 52 (61.9%), and bronchiectasis 27 (32.1%). Treatment results in the NTM treatment group were as follows: ongoing treatment 14 (10.4%), cure 64 (47.4%), default 33 (24.4%), exitus 19 (14.1%), recurrence 3 (2.2%), and refractory disease 2 (1.5%). Conclusion: This is a large case series evaluating the clinical significance of NTM growths and NTM treatment in Turkey. The clinical significance of NTM growth in respiratory samples is low. Treatment success rates of NTM patients who are treated are low. Treatment defaults and mortality rates are high. New drugs and new regimens are needed.
Keywords: Nontuberculous mycobacteria, pulmonary infection, species, sputum, treatment outcome
Nontuberculous mycobacteria (NTM) refer to mycobacterial species collectively excluding the Mycobacterium tuberculosis (TB) complex and Mycobacterium leprae.[1],[2] Although most of the NTM species have been defined as being nonvirulent or having a very low virulence in humans, the changing epidemiology of NTM has also been emphasized over the last two decades.[3],[4] Accordingly, management of NTM infections has become a challenging area for chest physicians, necessitating large-scale studies investigating the sophisticated aspects of increasingly prevalent infections related to NTM species.
While the epidemiology of NTM infections varies largely depending on the geographical regions, a global increase in the incidence of pulmonary NTM infections has recently been reported.[5],[6] A trend to use immunosuppressive drugs more often for various diseases, increase in life expectancy of patients suffering from chronic diseases, and changing trends in HIV infections are considered to be factors accounting for this increase.[7],[8]
The changes in environmental factors along with increased awareness of clinicians are also considered to contribute to the increasing prevalence and incidence of NTM pulmonary infections.[6] Furthermore, it is crucial to emphasize the role of the remarkable advances in molecular diagnostic methods in easier and unambiguous identification of NTM bacteria up to species level.[9]
Mycobacterium avium complex (MAC), Mycobacterium kansasii, Mycobacterium abscessus, and Mycobacterium fortuitum are the most frequently isolated mycobacteria in NTM pulmonary infections. Nonetheless, in addition to the geographical variation in the prevalence of NTM, the clinical presentations, treatment regimens as well as treatment responses also differ greatly depending on NTM species.[2] Thus, the heterogeneous epidemiology of NTM isolations and different clinical outcomes of NTM infections highlight the importance of specific management strategies for various species.
The aim of the present study was to evaluate the clinical significance of isolation of NTM from the sputum and to assess radiological findings, treatment regimens, and response to treatment in patients diagnosed with NTM pulmonary infection.
MethodsStudy population
A total of 1061 cases who have a NTM isolate in sputum were included in this retrospective study conducted at a tertiary care chest clinic between 2009 and 2020.
Study objectives
The primary objective of the study was to evaluate the clinical significance of NTM isolations in respiratory samples. The secondary objective was to evaluate the resistance results, treatment regimens, and treatment outcomes of those treated for NTM disease. The subjects were classified into 3 groups; those who received treatment for NTM disease (n = 135), a group of NTM infected/colonized patients who followed up with no treatment (n = 690), and a group of patients from whom Mycobacterium tuberculosis 
mplex (MTC) were isolated and treated with TB treatment (n = 236).
The study was conducted in accordance with the ethical principles stated in the “Declaration of Helsinki” and approved by the institutional ethics committee (protocol number: 116.2017.105).
Study parameters
Data on definition of disease, administered drugs, radiological and bacteriological findings, comorbid diseases, treatment regimens, and treatment outcomes were retrieved from hospital medical records.
Diagnostic tests
Each and every MGIT tube that flagged positive and Lowenstein–Jensen slant with visible colonies was subjected to p-nitro-alpha-acetylamino-beta-hydroxypropiophenone (NAP) and rapid immunochromatographic testing (ICT).[10]
The ICT was used for partial identification of mycobacterial isolates and discerning NTM spp. from MTC. In the event, rapid partial identification tests were reminiscent of NTM, the cultures were referred to Molecular Mycobacteriology Laboratory, Aziz Sancar Institute of Experimental Medicine, Istanbul University, where isolates were subjected to a serial testing of hsp65 PCR restriction analysis followed by 16S rDNA gene sequencing if NTM strain(s) could not be identified up to the species level by using hsp65PCRREA alone. If hsp65PCRREA method would identify an isolate as MTC further identification within the complex was performed by using spoligotyping.
The Ministry of Health General Directorate of Public Health National TB Reference Laboratory was also utilized for the classification of NTM species and for the conduction of resistance tests prior to the initiation of treatment.
Diagnosis and definitions
Diagnosis was established according to the American Thoracic Society (ATS) guidelines. The recommended diagnostic criteria for NTM pulmonary disease are expected to meet the clinical, microbiologic, and radiological criteria.[1],[2]
In subjects whom MTC was isolated and treated with TB treatment, patients with one NTM culture-positive sample and no supportive clinical and radiological findings were followed without NTM treatment, while identification of NTM was performed if the clinician was decided to identification.
Treatment approaches
We make the decision to initiate treatment in accordance with ATS recommendations. Patients with single NTM culture growth were followed and patients with multiple NTM culture growth having more potential risks than benefits of therapy despite multiple NTM culture growths were followed without treatment as recommended by ATS guideline.[2] Treatment regimens are formed according to the results of the drug susceptibility test. The drug sensitivity tests are performed after the treatment decision. We establish a treatment regimen including sensitive drugs that are detected after drug sensitivity tests. The treatment was continued for 12 months following the microbiologic culture conversion. Outpatients were followed up on a monthly basis and treatment outcomes were recorded. Patients traveling long distances to the hospital were evaluated in every 2–3 months and information from TB dispensaries' files were also recorded. Subjects receiving no treatment were also followed up every 2–3 months.
Treatment outcome
The culture conversion, microbiological cure, cure, clinical cure, treatment failure, recurrence, relapse, and reinfection were considered in accordance with the described criteria.[11]
ResultsDemographic and clinical characteristics in the groups
The characteristics of overall study population are shown in [Table 1]. The mean ± SD age of patients was 53.88 ± 16.45 years, and 749 (70.6%) were male. The subjects were classified into 3 groups; patients with NTM infection who received treatment (n = 135), and those followed up without treatment (n = 690) and a last group of patients with Mycobacterium tuberculosis complex strains were isolated and received TB treatment (n = 236).
Table 1: Demographic and clinical characteristics overall and in treatment groupsRespiratory comorbidities were evident in 37 (27.4%) patients in the NTM treatment group and 322 (46.7%) in the nontreatment NTM group. Previous TB treatment history had 51 (37.8%) in the NTM treatment group whereas 93 (13.5%) in the nontreatment NTM group. In the NTM treatment group, thorax CT imaging in 84 patients revealed nodule: 38 (45.2%), consolidation: 46 (54.8%), cavity: 52 (61.9%), and bronchiectasis: 27 (32.1%) [Table 1].
In total, 278 (26.2%) out of 1061 cases had identified, and the most frequent species were MAC (81; M. avium: 39, Mycobacterium intracellulare: 39, and MAC: 3), M. abscessus (67), M. kansasii (48), Mycobacterium fortuitum (23), Mycobacterium chelonae (12), Mycobacterium gordonae (11), and Mycobacterium szulgai (11).
In the most frequent species, in MAC species, 64 (79%) out of 81 cases had multiple positive and 56 (69.1%) of 81 cases were decided NTM treatment. M. abscessus species, 50 (74.6%) out of 67 cases had multiple positive, 22 (32.8%) of 67 cases were decided NTM treatment. M. kansasii species, 37 (77.1%) out of 48 positive cases had multiple positive, 41 (85.4%) of 48 cases were decided NTM treatment. M. fortuitum species, 12 (52.2%) out of 23 cases had multiple positive, 5 (21.7%) of 23 cases were decided NTM treatment. M. szulgai species, 9 (81.8%) out of 11 cases had multiple positive, 7 (63.6%) of 11 cases were decided NTM treatment. M. chelonae species, 7 (63.6%) out of 12 cases had multiple positive, and no case was considered to start treatment. M. gordonae species, 4 (36.4%) out of 11 cases had multiple positive, no case was considered to start treatment. M. lentiflavum species, 2 (28.6%) out of 7 cases had multiple positive, no case was considered to start treatment. M. triplex species, 2 (66.6%) out of 3 cases had multiple positive, 3 (100%) cases were considered to start treatment.
In the NTM treatment group, 116 out of 135 (85.9%) patients had multiple culture positivity.
The most frequent species within the NTM treatment group were MAC (56; M. avium: 27, M. intracellulare: 27, and MAC: 2), M. kansasii (41), and M. abscessus (22) [Table 2].
In the nontreatment NTM group, 573 out of 690 (83.4%) patients had only one single-culture positivity. One hundred and seventeen (16.6%) out of 690 patients had multiple culture positive. The benefit and harm of starting treatment were evaluated, and it was decided not to start treatment in 117 (16.6%) out of 690 patients with multiple culture NTM cases. Fifty-two (44.4%) out of 117 patients had been identified. The most frequent species M. abscessus (23), M. intracellulare (7), M. avium (5), M. fortuitum (4), M. gordonae (3), and M. szulgai (3).
In the TB treatment group, all patients have at least one culture MTC positive. They had treated TB treatment 154 (65.3%) out of 236 patients had only one single NTM positive. Eighty-two (34.7%) out of 236 patients had multiple NTM positive. Twenty-eight (34.1%) out of 82 patients had identified. In these cases, the most frequent species were M. abscessus (10), M. chelonae (4), and M. fortuitum (3). They had no clinical and radiologic deterioration, they had colonization accepted, no NTM treatment needed.
Treatment results in the NTM treatment group were as follows: ongoing treatment: 14 (10.4%), cure: 64 (47.4%), default: 33 (24.4%), exitus: 19 (14.1%), recurrence: 3 (2.2%), and refractory disease: 2 (1.5%) [Table 3].
Drug resistance and treatment outcomes in NTM species
Among subjects receiving NTM treatment, 22 patients were infected with M. abscessus. Drug susceptibility testing was performed in 11 of these subjects. M. abscessus species were resistant to doxycycline (n = 8), ciprofloxacin (n = 7), cefoxitin (n = 8), trimethoprim/sulfamethoxazole (n = 6), imipenem (n = 6), moxifloxacin (n = 6), tobramycin (n = 5), linezolid (n = 2), and clarithromycin (n = 1). The major drugs used in the treatment of M. abscessus infections in the study were clarithromycin (n = 21), amikacin (n = 19) and linezolid (n = 17), tigecycline (n = 7), and moxifloxacin (n = 6), rifampicin (n = 3), M. abscessus patients' treatment results were as follows: cure: 15 (68.2%), default: 2 (9.1%), exitus: 4 (18.2%), and recurrence: 1 (4.6%) [Table 4].
Table 4: Drug resistance and treatment outcomes in nontuberculous mycobacteria speciesAmong subjects receiving NTM treatment, 5 patients were infected with M. fortuitum. Drug susceptibility testing was performed in 2 out of 5 subjects with M. fortuitum infection and resistance to clarithromycin (n = 2), amikacin (n = 2), and ciprofloxacin (n = 2) was detected. Culture conversion was obtained in 3 (60%) patients, 2 (40%) patients were defaulters, and exitus was 1 (20%) patient [Table 4].
Among subjects receiving NTM treatment, 27 patients were infected with M. avium.
Drug susceptibility testing for M. avium species was performed in 16 out of 27 subjects and revealed resistance to linezolid (n = 8), ethambutol (n = 8), moxifloxacin (n = 7), ciprofloxacin (n = 6), amikacin (n = 6), ethionamide (n = 4), streptomycin (n = 4), and rifampicin (n = 4). The main drugs used in the treatment were clarithromycin (n = 25), rifabutin (n = 15), amikacin (n = 12), moxifloxacin (n = 11), ethambutol (n = 11), rifampicin (9), linezolid (n = 7), and protionamide (n = 3). Treatment results were recorded as follows: cure: 10 (37.1%), default: 9 (33.3%), exitus: 4 (14.2%), recurrence: 1 (3.7%), and ongoing treatment: 3.
Among subjects receiving NTM treatment, 27 patients were infected with M. intracellulare, and drug susceptibility testing in 21 subjects demonstrated resistance to moxifloxacin (n = 13), linezolid (n = 13), amikacin (n = 12), ciprofloxacin (n = 9), ethambutol (n = 7), rifampicin (n = 5), clarithromycin (n = 4), and ethionamide (n = 3). In the treatment of the subjects, clarithromycin (n = 20), ethambutol (n = 18), rifabutin (n = 14), moxifloxacin (n = 12), linezolid (n = 9), rifampicin (n = 8), and amikacin (n = 6) were used. Treatment results were as follows: cure: 7 (25.9%), default: 9 (33.3%), exitus: 4 (14.2%), recurrence: 1 (3.7%), refractory disease: 2 (7.40%), and ongoing treatment: 4.
Out of 3 patients with MAC infection, 2 patients had undergone drug susceptibility testing and were resistant to clarithromycin (n = 2), amikacin (n = 1), and ethionamide (n = 1). Mortality was reported in 1 subject and cure was demonstrated in 1 patient.
Among subjects receiving NTM treatment, 41 patients were infected with M. kansasii. Drug susceptibility testing was performed in 25 out of 41 subjects with M. kansasii infection and resistance to ciprofloxacin (n = 10), amikacin (n = 5), moxifloxacin (n = 4), rifampicin (n = 4), ethambutol (n = 3), ethionamide (n = 2), streptomycin (n = 2), and TMP-SMX (n = 2) was detected. Isoniazid (n = 34), rifampicin (n = 26), ethambutol (n = 26), clarithromycin (n = 18), rifabutin (n = 9), linezolid (n = 3), and ciprofloxacin (n = 2) were the treatment regiments frequently used for M. kansasii infection. Treatment results were recorded as follows: cure: 23 (56.1%), default: 7 (17.1%), exitus: 4 (9.8%), and ongoing treatment: 7 (30.4%) [Table 4].
Among subjects receiving NTM treatment, 7 patients were infected with M. szulgai. Drug susceptibility testing was performed in 3 out of 7 subjects with M. szulgai infection and resistance to ciprofloxacin (n = 2), ethambutol (n = 1), rifampicin (n = 1), rifabutin (n = 1), streptomycin (n = 1), ethionamide (n = 1), and moxifloxacin (n = 1) was detected. Clarithromycin (n = 5), moxifloxacin (n = 4), amikacin (n = 3), isoniazid (n = 2), rifampicin (n = 2), ethambutol (n = 2), pyrazinamide (n = 2), rifabutin (n = 2), TMP-SMX (n = 1), and linezolid (n = 1) were the regimens frequently used in the treatment patients with M. szulgai. Treatment results were reported as default: 4 (57.1%) and cure: 3 (42.9%) [Table 4].
Among subjects receiving NTM treatment, 3 patients were infected with M. triplex. In subjects with M. triplex infection, drug susceptibility testing was performed in all cases and resistance to ciprofloxacin (n = 1), ethambutol (n = 1), amikacin (n = 1), streptomycin (n = 1), and rifampicin (n = 1) was detected. Treatment results in 3 patients included cure: 2 (66.7%) and default: 1 (33.3%).
DiscussionClinical significance and treatment decision
The importance of NTM isolation in the culture of respiratory specimens should be interpreted according to the number of NTM-positive cultures and the characteristic of the NTM-specific strain isolated in individuals meeting the ATS diagnostic and radiological criteria.[7] In studies, 14-21% of patients who were positive for pathogenic NTM in a single sputum culture were diagnosed with NTM lung disease during follow-up of 16 months.[12],[13] Tsukamura evaluated the occurrence of a new cavitary (or infiltrative) lesion in 299 patients in whom the MAC was isolated once or more in sputum samples. They reported that 114 had growth in a single culture, while only 2 (2%) had cavitary lesions and a cavitary lesion was detected in 181 (98%) of 185 patients who had growth in two or more sputum cultures.[14] In a study from the USA on assessment of NTM-positive samples in sputum cultures among 230 patients, only 78 (33.9%) patients met all three ATS/IDSA microbiological, radiological, and clinical criteria for the diagnosis of NTM lung disease.[2]
In our study, 135 (%12.7) out of 1061 study cases was decided NTM treatment. Patients who were decided to receive NTM treatment were included in the NTM-treated group. In the NTM treatment group, 113 out of 135 (83.7%) patients had multiple culture positivity. In the group followed without treatment, growth in a single sample was detected in 573 (83.4%). The most frequent species within the NTM treatment group were MAC (n = 56; M. avium: 27, M. intracellulare: 27 and MAC: 2), M. kansasii (n = 41), and M. abscessus (n = 22).
In a study by Koh et al., 481 patients with MAC lung disease who were treated with antibiotics for ≥ 12 months were evaluated. Of 481 patients, 278 (58%) had noncavitary nodular bronchiectasis (NB), 80 (17%) had cavitary NB disease, and 123 (25%) had fibrocavitary disease. The NB form was found to be a significant independent risk factor for the recurrence of NTM lung disease. In those with recurrent MAC lung disease of the same species, bacterial genotyping revealed that 74% of cases were due to reinfection and 26% were due to relapse.[15] In another study by Koh et al.,[14] 44 patients with M. abscessus lung disease treated with antibiotics for ≥ 12 months were evaluated. After successful completion of antibiotic therapy, M. abscessus lung disease recurred in 5 (15%) patients.[14] In our study, In the NTM treatment group, previous history of NTM treatment was noted in 19 (14.1%) patients.
The pathogenicity of NTM species may differ between geographic regions.[7]
The pathogenicity of NTM varies considerably from organisms such as M. gordonae, which rarely causes disease in humans, to M. kansasii, which should generally be considered pathogenic.[7] In our study, species were identified in 278 (26.2%) of 1061 individuals. Species identification was made by the clinician's decision based on clinical significance. Commonly detected species were MAC (n = 81; M. avium: 39, M. intracellulare: 39, MAC: 3), M. abscessus (n = 67), and M. kansasii (n = 48). The clinical significance was detected to be high for MAC, M. kansasii, M. szulgai, and M. triplex in our study. The NTM treatment was considered for 56 (87.5%) out of 64 positive cases regarding MAC species, for 41 (85.4%) of 48 multiple positive cases regarding M. kansasii species, and for 7 (63.6%) of 11 multiple positive cases regarding M. szulgai species. In M. triplex species, 2 (66.6%) out of 3 cases had multiple positive and 3 cases (100%) were considered to start treatment. The decision of treatment initiation was lower in those who had M. abscessus growth, with consideration of NTM treatment in 22 (32.8%) of 67 positive cases in M. abscessus species. Because of the high resistance rates of M. abscessus species and the low number of sensitive drugs, it was decided to follow up without treatment. In our study, M. fortuitum was found to be of low clinical significance as a causative agent of lung disease. Contamination was considered colonization. Clinical significance was low in M. fortuitum species and NTM treatment was decided in 5 (21.7%) of 23 multiple positive cases. Clinically significant lung disease was not considered for M. chelonae, M. gordonae, and M. lentiflavum. Colonization was considered contamination. No treatment was considered. For M. chelonae species, 7 (63.6%) of 12 cases had multiple positive, and none of the cases were considered to start the treatment. For M. gordonae species, 4 (36.4%) of 11 cases had multiple positive, and no case was considered to start treatment. For M. lentiflavum species 2 (28.6%) of 7 cases had multiple positive, and no case was considered to start treatment.
In Taiwan, 305 (62.5%) of 488 patients with MAC lung disease who met ATS/IDSA disease criteria and were followed for at least 1 year had disease progression. Progression was higher in patients with positive acid-fast bacillus smear, fibrocavitary disease, or more extensive radiology.[15] According to the ATS guideline, the decision to initiate antimicrobial therapy for NTM lung disease should be individualized based on clinical factors, NTM species, and patient characteristics. Factors associated with poor prognosis were cavitary disease, low body mass index, low albumin, and/or high inflammatory markers.[2] In our study, in subjects who received NTM treatment, radiological findings revealed cavity in 52 (61.9%), consolidation in 46 (54.8%), nodule in 38 (45.2%), and bronchiectasis in 27 (32.1%) subjects. In our study, the treatment decision was based on the degree of disease, presence of cavity in radiology, number of sensitive drugs in drug sensitivity tests according to NTM types and was made by taking the patient's opinion, in terms of underlying comorbidities, drug side effects and whether the patient can withstand long-term treatment, given that suboptimal treatment results and reinfection with another species is frequent (nodular-bronchiectasis). We noted that the rate of treatment decision is low. In our study group, 117 (16.6%) out of 690 had multiple isolate, they were preferred “watchful waiting” and the treatment decision to be made by a specialist physician, according to ATS guideline.[2]
In a study on the risk of hospitalization in older adults with NTM lung disease, a total of cases and matched controls (mean age, 76.6 years; 70% females) were evaluated, particularly pulmonary comorbidities were found to be higher in the case group than in the control group (COPD 81.1% vs. 17.7%; bronchiectasis 44.6% vs. 0.6%). Also, all-cause hospitalization in NTM-PD patients was 1.2 times higher than in the control group.[16] In our study, the mean age of patients was 53.88 ± 16.45 years overall and was 51.11 ± 17.15 years in those who received NTM treatment. There was a male dominance, with 749 (70.6%) males in those with NTM growth in respiratory samples and 117 (86.7%) males in patients who received NTM treatment. Respiratory comorbidities were detected in 458 (43.2%) of the subjects with NTM growth in all respiratory samples and in 37 (27.4%) of patients initiating NTM treatment. Since our hospital is a tertiary chest disease hospital, our study group consists of participants who were admitted to the hospital with respiratory comorbidities. In our study, previous TB treatment history was present in 187 (17.7%) of the total cases, 51 (37.8%) of the patients who received NTM treatment, and 93 (13.5%) of the untreated group.
In a retrospective study from Taiwan on the prevalence and clinical effect of NTM in 2133 patients with culture-confirmed pulmonary TB, NTM was detected in 48 (2.3%) patients as multiple and in 106 (5.0%). Patients with multiple isolates of NTM were more likely to be symptomatic, seek medical assistance early, have cavity, smear-positive respiratory samples, and receive longer anti-TB therapy than those with a single/without isolate.[17] In our study, growth of a single NTM sample during TB treatment was high (154 [65.3%]) and considered contamination during treatment. In those with multiple growths, MTC was detected, TB treatment was completed, and cases with single or multiple NTM growths were followed up. Patients who receive NTM treatment were included in the NTM-treated group also. In the TB treatment group, all patients had at least one culture MTC positive; 82 (34.7%) of 236 patients had multiple NTM positive and 28 (34.1%) of 82 patients had identified. In these cases, the most frequent species were M. abscessus (n = 10), M. chelonae (n = 4), and M. fortuitum (n = 3). They had no clinical and radiologic deterioration, considered to have colonization and not to need NTM treatment. Differentiating TB disease from NTM lung disease can be difficult and requires careful clinical evaluation, collaboration with laboratory colleagues, and the use of available molecular diagnostic tools. TB treatment was given priority. After the completion of TB treatment, NTM was evaluated for lung disease.
Resistance test results and treatment outcome
According to the recommendations of the ATS guideline; the drug susceptibility test should be performed at the beginning of the treatment and if the culture positivity continues despite receiving treatment for 6 months, it should be repeated before the treatment.[2] In our cases, drug susceptibility testing has been performed before the initiation of treatment in accordance with the recommendation of ATS in recent years. Drug susceptibility testing was performed before the treatment in most of the cases. Unlike ATS recommendations, broad-spectrum drug susceptibility testing is performed. Drug susceptibility tests were performed in 16 (59.3%) of 27 people with M. avium lung disease, 21 (77.8%) of 27 people with M. intracellulare lung disease, and 25 out of 41 people with M. kansasii lung disease.
In our study, treatment results in the NTM treatment group were ongoing treatment in 14 (10.4%) patients, cure in 64 (47.4%), default in 33 (24.4%), exitus in 19 (14.1%), recurrence in 3 (2.2%), and refractory disease in 2 (1.5%) patients. The dropout rates due to drug side effects during treatment were high. The rates seemed to be high due to comorbid diseases. The treatment response of our patients was evaluated clinically, radiographically, and microbiologically.
Medications used to treat NTM lung disease are often associated with adverse reactions. A recent randomized clinical trial reported that >90% of subjects in each arm reported an adverse reaction induced by treatment.[18] Our patients were evaluated every month under close follow-up as we think that rapid identification and management of an adverse reaction would likely reduce the risk of treatment for the patient and possibly increase the probability to complete the treatment. In our study, the dropout rates were found to be high due to drug adverse reactions and the cost of the patient's treatment in drug supply. In a retrospective cohort study of Cheng et al.[19] from Shanghai, the treatment success rate was significantly higher in M. kansasii (89.9%)-infected patients than MAC (65.0%, P < 0.001) and M. abscessus (36.1%, P < 0.001). Risk factors for treatment failure were pathogenic NTM types (M. abscessus: P <0.001; MAC: P <0.001), high ESR (P < 0.001), re-treatment (P < 0.001), and middle-aged or elderly (P = 0.021 for > 60 years of age and P = 0.034 for 45–60 years of age).[19] In a retrospective analysis of 203 patients with MAC-pulmonary disease regarding the impact of emphysema on mortality, emphysema detected by computed tomography was reported to be associated with mortality in MAC-PD.[20] In a study investigating the prognostic factors associated with long-term mortality in 1445 newly-diagnosed previously untreated NTM-pulmonary patients, mortality was reported to differ by species, and when compared to M. avium, M. intracellular was found to be more fatal (Hazard ratios [HR]: 1.40, 95% confidence interval [CI] 1.03–1.91). Mortality-related factors included M. abscessus (aHR: 2.19, 95% CI: 1.36–3.51), the cavitary nodular bronchiectatic form (aHR: 1.70, 95% CI: 1.12–2.59), and the fibrocavitary form (aHR: 2.12, 95% CI: 1.57–3.08).[21] In a systematic review, continuous sputum culture conversion incidence rates were reported to be 0.38 (0.25–0.52) for macrolide-free regimens and 0.54 (95% CI: 0.45–0.63) for macrolide-containing regimens.[22] In another systematic review of 42 studies (18 retrospective, 18 prospective, and 6 randomized studies), treatment success with macrolide-containing regimens was reported to be 52.3% (95% CI: 44.7%–59.9%), while increased to 61.4% with ATS/IDSA 3-drug regimen and to 65.7% if treated for at least 12 months.[23]
In MAC lung disease, retrospective case series have demonstrated that in vitro resistance to clarithromycin is associated with worse outcomes than cases susceptible to clarithromycin.[24],[25] For MAC cases of disease, the sputum culture conversion rate was 80% when macrolide sensitive[26],[27] and 5%–36% when macrolide resistant.[28],[29],[30] As our approach is to perform susceptibility tests to all drugs in cases with MAC lung disease, drug susceptibility testing was performed for all drugs. The drugs used in the treatment were selected from sensitive, moderately resistant, and borderline resistant drugs according to the MIC value. For M. avium lung disease, the drugs used in the treatment were selected as those susceptible to resistance tests including clarithromycin (n = 25), rifabutin (n = 15), amikacin (n = 12), moxifloxacin (n = 11), ethambutol (n = 11), and rifampicin (n = 9). Treatment results included cure in 10 (37.1%) patients and default in 9 (33.3%). In the treatment of the subjects with M. intracellulare, clarithromycin (n = 20), ethambutol (n = 18), rifabutin (n = 14), moxifloxacin (n = 12), linezolid (n = 9), rifampicin (n = 8) and amikacin (n = 6) were used. Treatment results were cure in 7 (25.9%) patients, and default in 9 (33.3%).
For M. kansasii lung disease, resistance to rifampicin has been associated with treatment failure.[2] Our approach was based on the use of a daily treatment regimen in M. kansasii lung disease. After the decision of M. kansasii lung disease treatment, drug susceptibility testing was performed against all drugs, and sensitive drugs were used in the treatment regimen. Isoniazid (n = 34), rifampicin (n = 26), ethambutol (n = 26), clarithromycin (n = 18), rifabutin (n = 9) and were the regiments frequently used with M. kansasii infection. Treatment results were recorded as cure in 23 (56.1%) patients and default in 7 (17.1%). For M. kansasii treatment results if treatment regimen with the 3-drug administered for 9–18 months have been excellent cure rates 80-100% and if the regimen administered 12 months low relapse rates 2.56.6%.[31],[32],[33]
Current guidelines recommend treating pulmonary M. szulgai with a three-or four-drug regimen. Macrolides, fluoroquinolones, and standard TB drugs are often declared to be effective.[34] In our study, drug susceptibility testing was performed in 3 out of 7 subjects with M. szulgai infection clarithromycin (n = 5), moxifloxacin (n = 4), amikacin (n = 3) were the frequently used regimens in the treatment patients with M. szulgai. Treatment results of M. szulgai lung disease involved default in 4 (57.1%) patients and cure in 3 (42.9%) patients.
In one study, overall, 43 patients (21 men) were culture positive for M. triplex, pulmonary samples in 39 patients, and 17 (43.6%) NTM lung disease patients met the ATS criteria. Six patients were treated and it was successful in 5 patients. Four patients had localized extrapulmonary disease and were treated with surgical treatment ± antimicrobial therapy. DST suggests 93% of isolates are susceptible to macrolides.[35] In our study, among subjects receiving NTM treatment, 3 patients were infected with M. triplex. In subjects with M. triplex infection, drug susceptibility testing was performed in all cases and cure was noted in 2 (66.7%) patients and default was noted in 1 (33.3%) patient. In our study, the default rate were observed in patients infected with M. avium, M. intracellulare, M. szulgai then patients with M. kansasii and M. triplex isolates.
The ATS guideline recommended a macrolide-containing multidrug treatment regimen in patients with M. abscessus lung disease caused by inducible or nonmutation-resistant strains. M. abscessus lung disease caused by strains with inducible or mutational macrolide resistance, a macrolide-containing regimen was recommended if the drug is used for its immunomodulatory properties, although the macrolide is not accepted as an active drug in the multidrug treatment.[2] ATS noted that for M. abscessus lung disease treatment, the optimal drugs, regimens, and duration of treatment are not known. It is recommended that patients with M. abscessus lung disease caused by inducible (typically M. massiliense) or mutational macrolide resistant-free strains be treated at baseline with a macrolide-containing multidrug regimen containing at least 3 active drugs (guided by in vitro susceptibility). In patients with M. abscessus lung disease caused by strains with inducible (typically M. abscessus or M. bolletii) or mutational macrolide resistance, a regimen containing at least 4 active drugs whenever possible was recommended. In the ATS guideline, for the management of patients with M. abscessus lung disease, consulting a specialist is recommended.[2] In a retrospective cohort treated M. abscessus, the presence of in vitro resistance to clarithromycin was associated with worse outcomes.[36] Defining the exact subtype is useful. M. abscessus massiliense is associated with a dysfunctional erm (41) gene.[37] In a follow-up study, the culture conversion was more in M. abscessus subsp. massiliense than M. abscessus subsp. abscessus (85% vs. 25%, P < 0.001).[38] In our study, drug susceptibility testing was performed in 11 out of 22 patients. In our study, the major drugs used in the treatment of M. abscessus infections in the study were clarithromycin (n = 21), amikacin (n = 19), linezolid (n = 17), and tigecycline (n = 7) while the treatment outcome in M. abscessus patients involved cure in 15 (68.2%) patients, default in 2 (9.1%) patients, exitus in 4 (18.2%) and recurrence in 1 (4.6%) patient. In our study cure rate were high because of this cases very strictly selected cases for treatment.
Considering surgery, in selected patients with NTM lung disease, surgical resection was recommended as an adjuvant to medical therapy after expert consultation.[2] In our study, wedge resection of a M. avium patient was performed and surgery was performed. Although the number of sensitive drugs was 2 as clarithromycin and rifabutin, treatment of our patient resulted in cure.
ConclusionThe clinical significance of NTM growth is low. In cases with treatment indication, NTM lung disease treatment should be made with risk/benefit ratio. Since NTM lung disease is not considered a public health threat, its treatment is not compulsory, and the cost of treatment is not reimbursed by the Ministry of Health. As the cost of the treatment is high, there are difficulties in obtaining high-cost drugs during the treatment for at least 12 months. There are problems in the continuation of the treatment due to the drug-related side effects. Since the number of sensitive drugs is low, clinicians do not have the opportunity to choose alternative drugs for treatment. The treatment success rate is low and treatment discontinuation rates are high, and the new drugs and treatment regimens are needed. Most research priorities should be with new drugs, treatment regimens, shorter regimens, and better-tolerated regimens.
Acknowledgment
We would like to thank ASDETAE lab and Prof. Dr. Orhan Kaya Köksalan for identified NTM and drug resistance tests.
Ethics approval and consent to participate
Ethics committee approval of the University of Health Sciences, Süreyyapaşa Chest Diseases and Thoracic Surgery Training and Research Hospital was obtained for this study.
Financial support and sponsorship
Nil.
Conflicts of interest
There is no conflicts of interest.
References
留言 (0)