Mycobacterium abscessus treatment outcomes in cystic fibrosis: A single centre experience

•Treatment outcomes of Mycobacterium abscessus in cystic fibrosis remain poor.•Raised C-reactive protein is associated with worse M. abscessus treatment outcomes in cystic fibrosis.•Side-effect burden of M. abscessus antibiotic treatment is associated with poor treatment outcomes.•The optimal treatment regimen of Mycobacterium abscessus remains unknown. Mycobacterium abscessus is a multi-drug resistant species of non-tuberculous mycobacteria (NTM) that is increasingly emerging as a major threat to people with inflammatory lung diseases, such as cystic fibrosis (CF) [1Martiniano S. Nick J. Daley C. Nontuberculous Mycobacterial Infections in Cystic Fibrosis.Thorac Surg Clin. 2019; 29: 95-108Abstract Full Text Full Text PDF PubMed Google Scholar, 2Salsgiver E. Fink A. Knapp E. LiPuma J. Olivier K. Marshall B. et al.Changing epidemiology of the respiratory bacteriology of patients with cystic fibrosis.Chest. 2016; 149: 390-400Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar, 3Bryant J.M. Brown K.P. Burbaud S. et al.Stepwise pathogenic evolution of Mycobacterium abscessus.Science. 2021; 372: eabb8699Crossref Scopus (86) Google Scholar]. Despite increased awareness of the issues faced by M. abscessus and recent publications of NTM-pulmonary disease (NTM-PD) treatment guidelines for people with CF (pwCF) in 2016 [4Floto R.A. Olivier K.N. Saisman L. et al.US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis.Thorax. 2016; 71: i1-22Crossref PubMed Google Scholar] and the ATS/ERS/ESCMID/IDSA guidelines in 2020 [5Daley C.L. Iaccarino J.M. Lange C. et al.Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDSA clinical practice guideline.ERJ. 2020; 562000535Crossref Scopus (401) Google Scholar], the optimal treatment regimen for M. abscessus remains unclear and global treatment outcomes remain poor. There is hope that the advent of highly effective cystic fibrosis transmembrane regulator (CFTR) modulators may have the potential to reduce the rate of NTM acquisition by pwCF. Certainly, there are anecdotal case reports of pwCF with previously intractable NTM-PD caused by M. abscessus showing a remarkable improvement including, in some cases, eradication, following commencement of the CFTR modulator elexacaftor/tezacaftor/ivacaftor (ETI) [6McParland C. Nunn M. Marras T.K. Eradication of Mycobacterium abscessus infection in cystic fibrosis with initiation of Elexacaftor/Tezacaftor/Ivacaftor.J Cyst Fibros. 2024; 23: 38-40Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. However, the current literature describing the treatment outcomes for M. abscessus in pwCF, either pre- or post-modulator therapy remains limited. Despite the positive changes in the landscape facing CF, M. abscessus continues to be a source of significant morbidity and mortality. We conducted a retrospective cohort study reviewing electronic records for all pwCF at the Royal Papworth Hospital (RPH) between 1st January 2004 and 31st December 2016 to identify cases with at least one new isolation of M. abscessus from either sputum and/or bronchoalveolar lavage (BAL) samples. All microbiological samples were processed locally before speciation and sensitivity profiling was performed at the national reference laboratory. Treatment decisions, based on local guidelines, were adapted over time between 2004 and 2016, taking into consideration antimicrobial susceptibility testing and international consensus best practice. Successful treatment outcome was based on maintained culture negativity twelve months following treatment cessation. Approval for the study was granted through RPH clinical audit and research office. In total 50 pwCF were identified as having isolated M. abscessus on at least one microbiological sample, of which 42 pwCF met the ATS/IDSA criteria for treatment [7Griffith D.E. Aksamit T. Brown-Elliott B.A. et al.An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases.Am J Respir Crit Care Med. 2007; 175: 367-416Crossref PubMed Scopus (4863) Google Scholar]. Treatment was initiated in 40 (95 %) of the pwCF, with two not commencing treatment owing to pregnancy and psychological issues respectively. Analysis of the treatment outcomes for 39 pwCF was conducted (one subject was excluded as they had only been on treatment for 3 months at the time of data collection). Of the 39 pwCF who underwent at least 6 months of treatment, sustained culture conversion after 12 months of treatment cessation was achieved in 11 (28.2 %) pwCF. Antibiotic therapy used in the treatment regimens was generally in keeping with current guideline suggested therapy (Fig. 1). The mean duration of induction therapy for the 39 pwCF treated was 28.7 days and for continuation therapy 822.2 days. No specific antibiotic regimen was associated with a statistically significant rate of culture conversion within the first 6 months of treatment (Fig. 2). For those 11 pwCF achieving sustained culture conversion 12 months after treatment cessation, combination induction therapy with amikacin, tigecycline and imipenem was administered in 10 pwCF (90.9 %) for a mean duration of 22.9 days. Continuation regimen durations and antibiotic selection were more varied with mean duration of treatment of 656.4 days. Administration of nebulised amikacin was used for 9 pwCF (81.8 %) and macrolide therapy (either clarithromycin or azithromycin) administered for all 11 pwCF. Longitudinal data analysis was performed on the cohort evaluating the rate of FEV1 decline and change in C-reactive protein (CRP) as a marker of inflammation. Higher rates of CRP were noted in those pwCF who died because of M. abscessus infection. No statistical difference was observed in the rates of FEV1 decline when stratified by outcome (Fig. 3). Side-effects secondary to treatment were recorded in 34 pwCF (87.2 %) with the predominant issues being nausea (63.5 %), ototoxicity (30.7 %), bronchospasm (28.2 %) and liver function derangement (15.4 %). Additionally, those pwCF achieving sustained culture conversion had statistically less side-effects attributed to antibiotic treatment compared to those pwCF with chronic infection or those who died secondary to M. abscessus infection (p 0.0013). Our data adds to the understanding of the challenges faced in treatment M. abscessus in pwCF. An overall eradication rate of 28 % is in keeping with previous reported treatment outcome data [8DaCosta A. Jordan C.L. Giddings O. et al.Outcomes associated with antibiotic regimens for treatment of Mycobacterium abscessus in cystic fibrosis patients.J Cyst Fibros. 2017; 16: 483-487Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar,9Zomer D. van Ingen J. Hofland R. Epidemiology and management of nontuberculous mycobacterial disease in people with cystic fibrosis, the Netherlands.J Cyst Fibros. 2023; 22: 327-333Abstract Full Text Full Text PDF Scopus (0) Google Scholar]. Our analysis examined outcomes before the introduction of highly-effective CFTR modulator therapy. However, M. abscessus continues to be a concerning pathogen in pwCF. The decision of how long to continue treatment in pwCF with M. abscessus infection, particularly in the setting of ‘chronic infection’, is often challenging. Information relating to the treatment outcomes is therefore key in helping guide decisions around whether to initiate treatment and potentially what treatment to consider, particularly when treatment is often complicated by a significant side-effect burden. Analysis of the data from our cohort highlights the importance of side-effect burden when making treatment considerations, with the poorer treatment outcomes noted most likely thought to be related to either reduced adherence to treatment, side-effect driven suboptimal regimens and/or reduced antibiotic treatment duration. Whilst the association of CRP with a worse outcome is perhaps expected, the lack of correlation between FEV1 and NTM-PD is surprising given previous publications [10Qvist T. Taylor-Robinson D. Waldmann E. et al.Comparing the harmful of nontuberculous mycobacteria and Gram negative bacteria on lung function in patients with cystic fibrosis.J Cyst Fibro. 2016; 15: 380-385Abstract Full Text Full Text PDF PubMed Google Scholar]. This was felt likely because FEV1 decline in pwCF can be influenced by a range of factors unrelated to M. abscessus infection, for example: co-infection with other pathogenic organisms, in particular Pseudomonas aeruginosa; the presence of other co-morbidities such as diabetes and liver disease; and low body mass index. In our cohort, 25 pwCF (59 %) were co-infected with Pseudomonas aeruginosa and 11 (28 %) with Aspergillus fumigatus. Despite CFTR modulator therapy, there is a clear requirement for the optimisation of treatments targeting M. abscessus. Whether this relates to novel antibiotic regimens based on bacterial genomic factors or with novel antimicrobial therapies remains to be seen. Further understanding of the resistance mechanisms harboured by M. abscessus is likely to be integral to understanding the difficulties faced with treatment. The impact that CFTR modulator therapy has on NTM-PD in CF, particularly since the approval of ETI in 2019, will be a key area of ongoing research. Prospective analysis on the rates of M. abscessus acquisition and the development of ATS/IDSA criteria defined NTM-PD in pwCF receiving ETI will be key. IE, AF, CH were involved in conceptualising the study with IE writing the manuscript. Data curation and formal analysis was conducted by IE and AW. AF, CH, TB were all involved in reviewing and editing the manuscript. All authors have provided final approval for submission for publication. No external funding was sought for this study.