|Year : 2018 | Volume
| Issue : 2 | Page : 109-116
Mycobacterium abscessus complex: Natural history and treatment outcomes at a tertiary adult cystic fibrosis center
Emma Tippett1, Samantha Ellis2, John Wilson3, Tom Kotsimbos3, Denis Spelman4
1 Infectious Diseases Unit, Alfred Hospital, Melbourne, Victoria, Australia
2 Department of Radiology, Alfred Hospital, Melbourne, Victoria, Australia
3 Department of Respiratory Medicine, Alfred Hospital; Department of Medicine, Monash University, Melbourne, Victoria, Australia
4 Infectious Diseases Unit, Alfred Hospital; Department of Medicine, Monash University, Melbourne, Victoria, Australia
|Date of Web Publication||13-Jun-2018|
C/O Dr. Denis Spelman, Infectious Diseases Unit, The Alfred Hospital, P. O. Box: 315, Prahran, Victoria 3181
Source of Support: None, Conflict of Interest: None
Background: Mycobacterium abscessus complex (MAbsC) is a significant management dilemma when taking care of patients with cystic fibrosis (CF). Methods: We undertook a retrospective cohort analysis of all CF patients in whom MAbsC was isolated from 2005 to 2014. The natural history of MAbsC was determined and clinical factors examined in an attempt to predict transient compared to persistent colonization. Results: No correlation was found between recurrent MAbsC isolation and clinical factors such as body mass index, respiratory function, or age. Over two-thirds of our cohort cleared MAbsC colonization with no intervention and no consistent effect on lung function was identified. Four CF patients were initiated on treatment with only one successful outcome. Conclusion: This analysis demonstrates there are no clear predictors of those CF patients who will become persistently colonized with MAbsC and that a significant proportion will spontaneously clear carriage. As treatment success rate is poor, more work is urgently required in improving patient outcomes.
Keywords: Atypical mycobacterium, cystic fibrosis, Mycobacterium abscessus, nontuberculous mycobacterium
|How to cite this article:|
Tippett E, Ellis S, Wilson J, Kotsimbos T, Spelman D. Mycobacterium abscessus complex: Natural history and treatment outcomes at a tertiary adult cystic fibrosis center. Int J Mycobacteriol 2018;7:109-16
|How to cite this URL:|
Tippett E, Ellis S, Wilson J, Kotsimbos T, Spelman D. Mycobacterium abscessus complex: Natural history and treatment outcomes at a tertiary adult cystic fibrosis center. Int J Mycobacteriol [serial online] 2018 [cited 2018 Aug 17];7:109-16. Available from: http://www.ijmyco.org/text.asp?2018/7/2/109/234329
| Introduction|| |
Mycobacterium abscessus complex (MAbsC), an acid-fast, rapidly-growing atypical mycobacterium, is an opportunistic respiratory pathogen which presents significant management challenges in patients with cystic fibrosis (CF). The impact of pulmonary colonization may range from asymptomatic carriage to progressive, fulminant lung disease. Treatment commits a patient to a multi-antibiotic regimen, including parenteral agents, over months to years and puts the patient at risk of significant, potentially life-threatening side effects with low chance of successful clearance., In the CF population, determining whether MAbsC is contributing to lung disease is clouded by the presence of multiple pulmonary microbes and significant underlying CF-related bronchiectatic lung disease making radiological assessment difficult and the decision to treat imprecise. Previous isolation of MAbsC is a relative contraindication to lung transplantation which has major implications for CF patients with declining lung function.
As MAbsC infection is a relatively uncommon condition, it is not surprising that little is known about the pathogenesis, natural history of infection and optimal treatment regimens.In vitro antibiotic sensitivities do not correlate well with in vivo responses,, except potentially clarithromycin resistance at 14 days, and clinical practice guidelines have generally been inferred from more common atypical mycobacteria such as Mycobacterium avium complex. Furthermore, the population most at risk of infection with MAbsC, the CF population, has rarely been examined in isolation. The most recent and specific guidelines for atypical mycobacteria in CF, published by the European Cystic Fibrosis Society and the US Cystic Fibrosis Foundation, acknowledges that evidence regarding management and treatment of MAbsC is severely lacking. Several recent reports have suggested interpersonal and nosocomial transmission of MAbsC ,,, as well as high-level resistance to hospital-grade biocides, which has significant implications for infection control policies regarding patients with MAbsC.
This study was conducted at a tertiary hospital with one of the largest cohorts of adult CF patients under its care. We reviewed all CF patients with MAbsC-positive cultures isolated between 2005 and 2014. The questions asked were; what is the natural history of MAbsC colonization in patients with CF; are there differences in patient attributes that may contribute with spontaneous clearance of colonization; and finally, what were the treatment outcomes and complications of those in whom MAbsC treatment has been undertaken?
| Methods|| |
Cases were identified for this retrospective cohort study by searching the microbiology database for all positive acid–fast bacilli isolates between 2005 and 2014. Recommended practice at the Alfred Hospital for management of CF patients is to routinely test sputum samples from patients with chronic pulmonary disease on a yearly basis for mycobacterial microscopy and culture in keeping with the 2016 consensus recommendations. The medical history of each patient with a positive isolate was examined for further detail.
Patients were categorized based on the number of positive samples as follows: (a) single isolate followed by multiple negative tests (arbitrarily assigned 1 day of being culture positive), (b) multiple isolates with spontaneous clearance, and (c) persistent colonization, in an attempt to identify factors that may predispose to clearance versus persistence. Patients were deemed to have cleared MAbsC colonization if there were at least two negative sputum samples over a 6-month period. If the patient did not have repeat testing following the initial positive sample, they were excluded from analysis (n = 6). Information regarding patient demographics, pulmonary function, CF disease comorbidities, concurrent prophylactic antibiotic use, and other microbial isolates was collated. Finally, the clinical outcomes for patients in whom the decision to treat was made were reviewed in greater detail.
Differences between the groups were tested using GraphPad Prism 6.0 (Graft Pad Software, La Jolla, California, USA). using the nonparametric one-way ANOVA (Kruskal–Wallis) for numerical data and Fischer's exact Chi-squared test for categorical values. Statistical significance was considered P < 0.05. This study was conducted under Ethics Approval (project number 591/13). Informed consent was obtained due to the retrospective nature of this study.
| Results|| |
From January 2005 to December 2014, MAbsC was isolated from specimens from 45 individual patients [Table 1], the majority of whom had underlying lung disease such as CF (n = 26), chronic obstructive pulmonary disease (n = 6), or idiopathic bronchiectasis (n = 4). As MAbsC is of particular concern to those patients with CF, this cohort is the focus of further analysis.
|Table 1: Demographics of all patients from whom Mycobacterium abscessus complex has been isolated between January 2006 and December 2014|
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The major characteristics of those patients with CF, in whom MAbsC was isolated were collated [Table 2]. The median age of CF patients with MAbsC was 33.5 years (range 21–66) with a heavy male predominance of 19 of the 26 patients. The median forced expiratory volume in 1 s (FEV1) at time of the first isolate was 73% of normal (range 20%–100%). Subtyping was not available for the majority of isolates and was reported simply as MAbsC. Of the 12 isolates further subtyped, four were Mycobacterium massiliense and eight M. abscessus ssp. abscessus. Isolation of other nontuberculous mycobacterium was common. One death was reported in this CF cohort over the period studied.
|Table 2: Specific characteristics of individuals with cystic fibrosis in whom Mycobacterium abscessus complex was isolated|
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Risk factors of persistent Mycobacterium abscessus complex colonization
Patients were then classified into those in whom MAbsC was isolated only once, those in whom it was isolated multiple times and then subsequently spontaneously cleared, and in those with persistent colonization or progressing to treatment to assess for any factors that may protect against persistent colonization or contribute to spontaneous clearance. The factors examined included the duration from first positive specimen to the last, lung function at the time of first MAbsC isolation and nutritional status (body mass index) [Table 3]. CF-related issues were also examined such as the presence of insulin-dependent diabetes mellitus, pancreatic insufficiency, the use of inhaled and systemic steroids, and the use of prophylactic antibiotics oral azithromycin or inhaled tobramycin [Table 3]. Finally, other microbial isolates were also assessed [Table 4].
|Table 3: Characteristics of cystic fibrosis patients stratified by those with a single isolate, multiple isolates followed by spontaneous clearance, and those with persistent Mycobacterium abscessus complex colonization|
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|Table 4: Other microbial isolates detected in sputum of cystic fibrosis patients in whom Mycobacterium abscessus complex has been isolated|
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On average, MAbsC was isolated for approximately 1 year before becoming culture negative in those patients who spontaneously cleared MAbsC [Figure 1]. Those in whom only a single specimen was positive for MAbsC had better lung function than those who had prolonged MAbsC isolation (P< 0.01) [Table 3]. However, the group with the lowest FEV1 was able to clear MAbsC. There was no difference in nutritional status, the proportion of patients with insulin-dependent diabetes mellitus or pancreatic insufficiency. Inhaled steroids did not appear to be a risk factor for prolonged isolation of MAbsC. Similarly, the use of prophylactic antibiotics did not appear to be protective [Table 3]. Examination of other microbial isolates found in CF patients with MAbsC demonstrated similar rates of Pseudomonas spp., Staphylococcus aureus, and Aspergillus spp. [Table 4].
|Figure 1: Acid–fast bacilli testing within cohort. Cystic fibrosis patients were classified into three groups: top; single Mycobacterium abscessus complex specimen, middle; multiple Mycobacterium abscessus complex isolates then spontaneous clearance, and bottom; persistent Mycobacterium abscessus complex isolation. All acid–fast bacilli testing is plotted against time (years) relative to the initial Mycobacterium abscessus complex positive culture (solid red dots). Subsequent Mycobacterium abscessus complex isolates are represented with orange dots and other Mycobacterium isolates with solid blue dots. Open dots represent negative acid–fast bacilli culture. *Patients who underwent treatment|
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Mycobacterium abscessus complex colonization versus disease
We also examined the effect of MAbsC colonization on FEV1 preceding and following MAbsC isolation [Figure 2]. While being nonquantitative, there appeared no clear impact of MAbsC colonization on FEV1 for any of the groups, and in fact, those with persistent colonisations often had stable FEV1 during the period of being culture positive compared to the time before becoming culture positive.
|Figure 2: The effect of Mycobacterium abscessus colonization on pulmonary function. The effect of Mycobacterium abscessus colonization on pulmonary function was assessed by comparing the forced expiratory volume in 1 s (FEV1) of every respiratory function test (solid line) over time (years, note variable axis) during the period for which the patient was tested for Mycobacterium abscessus complex. The period during which the patient was positive for Mycobacterium abscessus complex is represented as transparent gray bars. Duration of Mycobacterium abscessus complex testing is represented by dashed line with gray circles representing each acid–fast bacilli test. Patients who underwent lung transplant or did not undergo a sufficient duration of pulmonary function tests are not presented here. *Patients who underwent treatment|
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Mycobacterium abscessus complex treatment outcomes
We further examined the treatment outcomes in those patients with CF in whom the decision to treat was made [Table 5]. Of the 26 patients with CF in whom MAbsC was isolated, the decision to treat was made in four, with three (patients 11, 14, and 32) being treated on two or more separate occasions. Indications for treatment included in preparation for lung transplant and posttransplant surgical site infection. The treatment backbone invariably included amikacin plus a macrolide and tigecycline or a second- or third-generation cephalosporin.
|Table 5: Treatment regimens and outcome of patients who underwent Mycobacterium abscessus treatment|
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Treatment outcomes were poor with significant side effects including fulminant hepatitis, thought to be due to tigecycline in setting of CF cirrhosis, and permanent severe senineurol hearing loss. The only patient who was successfully treated (patient 18) had only recently become colonized with MAbsC and treatment was supplemented with surgical resection and lung transplantation. It is interesting to note the positive outcome in this patient given MAbsC colonization is a relative contraindication to lung transplant. Patient 14 underwent treatment with novel CFTR potentiator (ivacaftor) did not clear MAbsC carriage despite a significant improvement in pulmonary function tests. The final patient, patient 32, was not known to be colonized with MAbsC before lung transplant. Following lung transplant, he was found to have multiple surgical site infections, including within the pulmonary vein anastomosis. He is currently undergoing treatment which has been supplemented with surgical resection of infected tissues.
| Discussion|| |
In this retrospective cohort study conducted at a large tertiary hospital with an adult CF unit, we examined all patients in whom MAbsC had been isolated over a 10-year period from between 2005 and 2014. As expected, MAbsC was predominantly found to be an opportunistic respiratory pathogen in patients with underlying pulmonary or immunological disease with patients with CF comprising the largest proportion. Our major findings in patients with CF include a relatively high rate of spontaneous clearance following prolonged isolation, no major clinical features determining those patients at risk of persistent colonization and no evidence of the contribution of MAbsC to significant progression of lung disease.
Within our cohort, a high proportion cleared MAbsC with no intervention; approximately one-third cultured MAbsC on only one occasion, one-third was positive for MAbsC for on average of 1 year before spontaneous clearance, and one-third was persistently colonized. The questionable significance of a single MAbsC isolated has been previously reported, however, to the best of our knowledge, this is the first description of a substantial proportion of CF patients spontaneously clearing MAbsC following prolonged colonization. These findings have implications on our understanding of the natural history of MAbsC colonization and the need to intervene with treatment. Furthermore, the interpretation of therapeutic studies needs to consider these findings given a significant proportion of patients will clear carriage irrespective of treatment. Examination of clinical factors including nutritional status, steroid use, and prophylactic antibiotics did not help predict those who are more likely to remain persistently colonized compared to those in whom colonization spontaneously resolves., Examination of larger cohorts of patients may uncover subtle trends not demonstrated within our relatively small sample size.
The effect of MAbsC on pulmonary function has previously been shown to cause a subtle acceleration in decline in FEV1 of <1% per year. Gross examination within our cohort on the effect of MAbsC colonization or clearance on FEV1 did not demonstrate any obvious patterns of exacerbations of pulmonary disease in the presence of MAbsC colonization or, alternatively, improvement in pulmonary function following clearance. Furthermore, several patients with persistent MAbsC colonization maintained stable lung function over many years suggesting that MAbsC may, in fact, be benign in some people.
Here, we observe treatment outcomes in the CF population are poor, with cure occurring in only one patient in whom treatment was supplemented with lung transplantation. In another patient, while the prognosis was poor, treatment directly contributed to hastening the patient's death. These examples highlight the importance of balancing the risks of treatment with the likely failure to cure MAbsC in CF patients. While inherently resistant to antimicrobial therapies, current evidence suggests that MAbsC demonstrates the greatest sensitivity to amikacin, cefoxitin, and clarithromycin.,In vitro antibiotic sensitivities have proved to be unreliable in directing antibiotic regimens and the description of the inducible macrolide resistance gene Erm found in M. abscessus spp. abscessus further complicates treatment decisions  as this accounts for a significant proportion of isolates found in Australia. As there are both regional difference of MAbsC burden and CF, treatment may need to be tailored to the local situation., New drug regimens for the treatment of MAbsC are sorely needed. Recent in vitro research suggests newer agents warranting further investigation include carbapenem/rifampicin combinations, inhaled antibiotics,,,, tigecycline,, and Mycobacterium leprae drug clofazimine.,, The novel MAbsC animal models recently described hold potential to improve our knowledge regarding antibiotic response of MAbsC.,,
| Conclusion|| |
For the clinician, patients in whom MAbsC is isolated are often a management dilemma. Differentiation between MAbsC colonization and disease involves some modalities including the patient's clinical status and radiological evidence of pathology. In the setting of CF, teasing out the contribution of MAbsC to pulmonary function decline given multiple microbial isolates and inherent radiological changes is highly challenging. Given a significant proportion of patients will either spontaneously clear carriage or have a benign course, careful watchful waiting is a feasible management plan, saving patients from the potential toxicities associated with treatment. To date, clinical outcomes following decision to treat are disappointing with only weak evidence for the currently accepted antibiotic regimens., Given that some studies report differing pathogenicity and response to treatment between M. abscessus ssp.abscessus and M. massiliense,,,, further research into clinical outcomes of MAbsC is required with delineation of subspecies. Clinical trials comparing antibiotic regimens would greatly improve evidence, however, are technically difficult given the relatively infrequent commitment to treat and the heterogeneity of the patient population. Furthermore, our data show interpretation of studies demonstrating “cure” following treatment should be carefully assessed given the natural history in this patient population demonstrating high rates of spontaneous clearance over time. Given the low rate of success with our current regimen, the decision to treat a CF patient with MAbsC is one that should be carefully balanced and further research to improve treatment outcomes is desperately needed.
E.T. collated and analyzed patient data, prepared the manuscript, and takes responsibility for the integrity of the data and accuracy of the data analysis. D.S. and T.K. were instrumental in study design, data interpretation, and manuscript preparation. J.W. was involved in data interpretation and manuscript preparation. S.E. was responsible for review and scoring of radiological chest imaging (data not included).
Special thanks to Felicity Finlayson and Elyssa Williams, Cystic Fibrosis Unit, Alfred Hospital, Australia, for data collection support and cross-referencing; Amanda Dennison, Infectious Diseases Unit, Alfred Hospital, Australia, for microbiology database search; Carmela Corallo, Head of Pharmacy, Alfred Hospital, Australia, for provision of drug administration history; Brigitte Borg, Pulmonary Lung Function Unit, Alfred Hospital, Australia for provision of lung function results and Prof. Allen Cheng, Alfred Hospital Infectious Diseases Unit, for intellectual input.
Financial support and sponsorship
E.T. was supported by the Alfred Hospital Junior Medical Work Force.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]