Inhaled therapies for NTM disease – The way forward?

Abstract

Despite improvements in the control of respiratory infections and life expectancy in cystic fibrosis (CF), highly resistant pathogens such as nontuberculous mycobacteria have emerged as an increasing challenge [[1]Floto R.A. Haworth C.S. The growing threat of nontuberculous mycobacteria in CF.J Cystic Fibrosis. 2015; 14: 1-2Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar]. Disease due to M. abscessus is of particular concern as it is associated with increased healthcare utilisation, accelerated lung function decline, impaired quality of life (QoL) [[2]Lee M. Sheng W. Hung C. Yu C. Lee L. Hsueh P. Mycobacterium abscessus complex infections in humans.Emerg Inf Dis. 2015; 21: 1638-1646Crossref PubMed Google Scholar], adverse impacts on post-lung transplant outcomes [[3]Smibert O. Snell G. Bills H. Westall G. Morrissey C. Mycobacterium abscessus complex - a particular challenge in the setting of lung transplantation.Expert Rev Anti Infect Ther. 2016; 14: 325-333Crossref PubMed Scopus (18) Google Scholar], and increased mortality [[2]Lee M. Sheng W. Hung C. Yu C. Lee L. Hsueh P. Mycobacterium abscessus complex infections in humans.Emerg Inf Dis. 2015; 21: 1638-1646Crossref PubMed Google Scholar]. Good quality evidence to support current treatment regimens is lacking, and access to effective antimicrobial treatment options is limited. In this issue of the Journal, Banaschewski and colleagues [[4]Banaschewski B. Verma D. Pennings L. Zimmerman M. Ye Q. Gadawa J. et al.Clofazimine inhalation suspension for the aerosol treatment of pulmonary nontuberculous mycobacterial infections.J Cyst Fibrosis. 2019; 18: 714-720Google Scholar] report on the development of clofazimine inhalation suspension (CIS). The authors demonstrate the in vitro activity of the suspension against both M. abscessus and M. avium, in vivo activity in murine infection comparable with oral clofazimine in both acute and chronic infection models, and four-fold higher intrapulmonary clofazimine concentrations achievable with inhalational suspension than with oral gavage administration. The authors are to be congratulated on providing hope for clinicians and patients longing for the large void of NTM therapies to be filled. Current guidelines involve prolonged multidrug regimens for the treatment of NTM pulmonary disease [[5]Floto R.A. Olivier K.N. Saiman L. Daley C.L. Herrmann J.-L. Nick J.A. 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: executive summary.Thorax. 2016; 71: 88-90Crossref PubMed Scopus (261) Google Scholar] and toxicity rates are especially high [[6]Park J. Cho J. Lee C.-H. Han S.K. Yim J.-J. Progression and treatment outcomes of lung disease caused by Mycobacterium abscessus and Mycobacterium massiliense.Clin Infect Dis. 2016; 64: 301-308Google Scholar]. Inhaled therapies for NTM control are particularly appealing to increase the drug concentration within the lungs and to reduce systemic exposure and the incidence of systemic side effects [[7]Quon B. Goss C. Ramsey B. Inhaled antibiotics for lower airway infections.Ann Am Thor Soc. 2014; 11: 425-434Crossref PubMed Scopus (127) Google Scholar]. Additionally mycobacteria tend to reside and proliferate within alveolar macrophages [[8]Aulicino A. Dinan A. Miranda-CasoLuengo A. Browne J. Rue-Albreacht K. MacHugh D. et al.High-throughput transcriptomics reveals common and strain-specific responses of human macrophages to infection with Mycobacterium abscessus smooth and rough variants.BMC Genomics. 2015; 16: 1046Google Scholar], and the uptake of drugs by macrophages is considered a crucial step in pathogen elimination. Previous studies have demonstrated that inhaled particles or vesicles are readily engulfed by alveolar macrophages [[9]Hickey A. Durham P. Dharmadhikari A. Nardell E. Inhaled drug treatment for tuberculosis: past progress and future prospects.J Control Rel. 2016; 240: 127-134Google Scholar], which should improve the concentration of antimicrobials within infected cells. Clofazimine, a rimophenazine dye, was originally developed as a treatment for tuberculosis (TB) and is also used as a treatment for leprosy [[10]Barry V. Conalty M. Gaffney E. Antituberculous activity in the phenazine series; isomeric pigments obtained by oxcidation of O-phenylenediamine derivatives.J Pharm Pharmacol. 1956; 8: 1089-1096Google Scholar,[11]Barry V. Belton J. Conalty M. Denneny J. Edward D. O’Sullivan J. et al.A new series of phenazines (Rimino-compounds) with high antituberculosis activity.Nature. 1957; 179: 1013-1015Crossref PubMed Scopus (187) Google Scholar]. Previous reports have documented its benefit in CF associated NTM infections [12Aznar M. Brode S. Mehrabi M. Marras T. Safety and effectiveness of clofazimine in nontuberculous mycobacterial lung disease.Can J Respir Crit Care Sleep Med. 2018; 2: 72-77Google Scholar, 13Martiniano S. Wagner B. Levin A. Nick J. Sagel S. Daley C. Safety and effectiveness of clofazimine for primary and refractory nontuberculous mycobacterial infection.Chest. 2017; 152: 800-809Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar, 14Jarand J. Davis J.P. Cowie R.L. Field S.K. Fisher D.A. Long-term follow-up of Mycobacterium avium complex lung disease in patients treated with regimens including clofazimine and/or rifampin.Chest. 2019; 149: 1285-1293Google Scholar]. Clofazimine has demonstrated synergistic activity in vitro against NTM and TB with antibiotics such as amikacin and bedaquiline [[15]van Ingen J. Totten S.E. Helstrom N.K. Heifets L.B. Boeree M.J. Daley C.L. In vitro synergy between clofazimine and amikacin in treatment of nontuberculous mycobacterial disease.Antimicrob Agents Chemother. 2012; 56: 6324-6327Crossref PubMed Scopus (102) Google Scholar,[16]Ruth M. Sangen J. Remmers K. Pennings L. Svensson E. Aarnoutse R. et al.A bedaquiline/clofazimine combination regimen might add activity to the treatment of clinically relevant no-tuberculous mycobacteria.J Antimicrob Chemother. 2019; 74: 935-942Google Scholar]. It is highly concentrated within macrophages [[17]Baik J. Rosania G. Macrophages sequester clofazimine in an intracellulare liquid crystal-like supramolecular organization.PloS ONE. 2012; 7e47494Crossref PubMed Scopus (59) Google Scholar], making it particularly appealing, but its uptake into tissues other than the lung may also account for its adverse effects over a long course of therapy (particularly skin gut and eyes) which have resulted in discontinuation rates of 5-33% in published studies of mycobacterial infections [[12]Aznar M. Brode S. Mehrabi M. Marras T. Safety and effectiveness of clofazimine in nontuberculous mycobacterial lung disease.Can J Respir Crit Care Sleep Med. 2018; 2: 72-77Google Scholar,[13]Martiniano S. Wagner B. Levin A. Nick J. Sagel S. Daley C. Safety and effectiveness of clofazimine for primary and refractory nontuberculous mycobacterial infection.Chest. 2017; 152: 800-809Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar,[18]Henkel A. Paulson M. Claypool R. Prevots D. Holland S. Olivier K. Safety and tolerability of clofazimine for the treatment of nontuberculous mycobacterial infections.Am J Resp Crit Care Med. 2012; 185A4038Google Scholar]. The preparation, clofazimine inhalation suspension (CIS) reported here, is a proprietary formulation whose major components include clofazimine, polysorbate 80, sodium chloride and water, giving a final concentration of 20mg/ml clofazimine. Interestingly the in vitro MICs for the CIS were lower than those of oral clofazimine for the 4 MAC and 4 M. abscessus strains tested, suggesting that the excipient may have additional beneficial effects against NTM. This has previously been reported for M. avium [[19]Masaki S. Sugimori G. Okamoto A. Imose J. Hayashi Y. Effect of Tween 80 on the growth of Mycobacterium avium complex.Microbiol Immunol. 1990; 34: 653-663Crossref PubMed Scopus (27) Google Scholar] along with documented effects against biofilm [[20]Munoz-Egea M. Garcia-Pedrazuela M. Mahillo-Fernandez I. Esteban J. Effect of antibiotics and antibiofilm agents in the ultrastructure and development of biofilms developed by nonpigmented rapidly growing mycobacteria.Microb Drug Resist. 2016; 22: 1-6Google Scholar]. Whilst quite crude measures of tolerability were used (change in weight and behaviour) and notably in mice, there didn’t appear to be any adverse effects when CIS was administered at a range of doses and for up to 28 days in this small animal model. CIS treatment compared to oral clofazimine led to greater reductions in bacterial recovery from lung tissue in both acute and chronic models of infection tested (murine models included SCID and CFTR-/- mice). Lung tissue levels following treatment were approximately four times greater following treatment of infection with CIS compared to oral clofazimine. Counter intuitively, there was a trend towards significantly more elevated plasma levels of clofazimine in the CIS treated mice compared to orally treated. This observation warrants further investigation as it implies absorption from the lung to the circulation, with potential for deposition in other tissues. As most of the systemic side effects occur after months of oral clofazimine treatment, the prolonged administration of CIS beyond 28 days may not necessarily be associated with lower rates of systemic toxicity. Interest in inhaled therapies for NTM disease has existed for some time. Retrospective studies first demonstrated some efficacy for inhaled amikacin in NTM disease, with 25-43% patients achieving persistently negative cultures in refractory NTM pulmonary disease (NTM-PD). However adverse events were common (50%), and in one study discontinuation occurred in 35% of participants due to side effects [[21]Olivier K. Shaw P. Glaser T. Bhattacharyya D. Fleshner M. Brewer C. et al.Inhaled amikacin for treatment of refractory pulmonary nontuberculous mycobacterial disease.Ann Am Thor Soc. 2014; 11: 30-35Crossref PubMed Scopus (114) Google Scholar]. In order to improve outcomes and reduce side effects a liposomal formulation of amikacin was developed (Arikayce; Insmed NJ USA). The success of this formulation in improving sputum conversion rates (29 v 9% at 6 months) in refractory patients with MAC infection, has led to the FDA approval of this drug for refractory NTM disease [[22]Griffith D.E. Eagle G. Thomson R. Aksamit T.R. Hasegawa N. Morimoto K. et al.Amikacin liposome inhalation suspension for treatment-refractory lung disease caused by Mycobacterium avium complex (CONVERT): a prospective, open-label, randomized study.Am J Respir Crit Care Med. 2018; 198: 1559-1569Crossref PubMed Scopus (97) Google Scholar]. In vitro and in vivo studies have demonstrated that this formulation is at least as effective as free (non-liposomal) amikacin [[23]Rose S. Neville M. Gupta R. Bermudez L. Delivery of aerosolized liposomal amikacin as a novel approach for the treatment of nontuberculous mycobacteria in an experimental model of pulmonary infection.PLoS ONE. 2014; 9Google Scholar] but with improved uptake by alveolar macrophages [[24]Zhang J. Leifer F. Rose S. Chun D.Y. Thaisz J. Herr T. et al.Amikacin liposome inhalation suspension (ALIS) penetrates non-tuberculous mycobacterial biofilms and enhances amikacin uptake into macrophages.Front Microbiol. 2018; 9: 915Crossref PubMed Scopus (54) Google Scholar,[25]Malinin V. Neville M. Eagle G. Gupta R. Perkins W. Pulmonary deposition and elimination of liposomal amikacin for inhalation and effect on macrophage function after administration in rats.Antimicrob Agents Chemother. 2016; 60: 6540-6549Crossref PubMed Scopus (20) Google Scholar]. Local oral and respiratory side effects were still quite common with this formulation (87.4%) compared with placebo (50%) [[22]Griffith D.E. Eagle G. Thomson R. Aksamit T.R. Hasegawa N. Morimoto K. et al.Amikacin liposome inhalation suspension for treatment-refractory lung disease caused by Mycobacterium avium complex (CONVERT): a prospective, open-label, randomized study.Am J Respir Crit Care Med. 2018; 198: 1559-1569Crossref PubMed Scopus (97) Google Scholar]. Nevertheless the clinical and commercial success of Arikayce provides enthusiasm in the field for further inhaled therapy in NTM-PD. Several other inhaled options with a potential role in the treatment of NTM are also under investigation. Nebulised azithromycin has been shown to aerosolise to particle sizes within the respirable range using different nebuliser devices [[26]Hickey A. Lyu D. Ashley E. Stout J. Inhaled azithromycin therapy.J Aerosol Med. 2006; 19: 54-60Crossref PubMed Scopus (37) Google Scholar]. Ciprofloxacin, a drug with poor oral bioavailability in NTM, has been tested in preclinical NTM models (dry powder nanocrystalline and liposomal formulations) in in vitro intracellular infection models and established biofilms of both M. avium and M. abscessus [[27]Blanchard J.D. Elias V. Cipolla D. Gonda I. Bermudez L.E. Effective treatment of Mycobacterium avium subsp. species hominissuis and Mycobacterium abscessus Species infections in macrophages, biofilm, and mice by using liposomal ciprofloxacin.Antimicrob Agents Chemother. 2018; 62Google Scholar]. The in vivo efficacy of liposomal ciprofloxacin against M. abscessus in murine models has also been recently reported [[28]Bermudez L. Blanchard J.D. Babrak L. Gonda I. Treatment of Mycobacterium avium subsp hominissuis (MAH) lung infection with liposome-encapsulatied ciprofloxacin resulted in significant decrease in bacterial load in the lung.Am J Resp Crit Care Med. 2015; 191: A6293Google Scholar,[29]Bermudez L.E. Palmer A. Blanchard J. Gonda I. Treatment of Mycobacterium avium subsp hominissuis (MAH) lung infections in mice with intranasally instilled liposomal ciprofloxacin in combination with clarithromycin and ethambutol.Am J Resp Crit Care Med. 2019; 199A2540Google Scholar]. Other inhaled therapies currently under investigation include nitric oxide [[30]Bentur L. Gur M. Masarweh K. Livnat-Levanon G. Gefen Y. Ashkenazi M. et al.Nitric oxide inhalation in cystic fibrosis patients infected with Mycobacterium abscessus complex: a prospective, open-labeled, Multi-center pilot study.Am J Resp Crit Care Med. 2018; 197: A5919Google Scholar,[31]Deppisch C. Herrmann G. Graepler-Mainka U. Wirtz H. Heyder S. Engel C. et al.Gaseous nitric oxide to treat antibiotic resistant bacterial and fungal lung infections in patients with cystic fibrosis: a phase I clinical study.Infection. 2016; 44: 513-520Crossref PubMed Scopus (50) Google Scholar] (AIT Therapeutics Inc) and GM-CSF [[32]Scott J. Ji Y. Kannan M. Wylam M. Inhaled granulocyte-macrophage colony stimulating factor for Mycobacterium abscessus in cystic fibrosis.Eur Respir J. 2018; 511702127Crossref PubMed Scopus (20) Google Scholar] (Savara Inc). There are significant hurdles to overcome however, in moving these new therapies to patients. The evaluation of a drug in vitro has not necessarily correlated with clinical outcomes in NTM. Broth microdilution, the hollow fibre model, and a number of different animal models have been trialled to evaluate the efficacy of drugs against NTM and to date, none has proven to correlate well with observed clinical outcomes. Pharmaceutical regulations require a drug to have a statistically significant benefit compare to placebo in well controlled clinical trials, to ensure these drugs are both efficacious and safe. These trials are extremely challenging as currently used treatment regimens are complex, often poorly tolerated, and involve multiple expensive and toxic drug combinations across both intensive and consolidation phases and for periods of >12 months. Finally, microbiological and clinical outcomes vary and it is likely that pathogen and host factors, such as differences in pharmacokinetics, play a role in successful treatment outcomes. Importantly, clinically meaningful endpoints include lung function, affected by co-pathogens (common, if not universal in people with CF) and underlying disease severity. A recent systematic review and meta-analysis revealed that NTM treatment combinations are often ineffective and may even worsen QoL [[33]Diel R. Ringshausen F. Richter E. Welker L. Schmitz J. Nienhaus A. Microbiological and clinical outcomes of treating non-Mycobacterium avium complex nontuberculous mycobacterial pulmonary disease: a systematic review and meta-analysis.Chest. 2017; 152: 120-142Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar]. The review strongly recommended that “clinical, functional and QOL parameters should be given more emphasis in the evaluation of treatment outcomes” and that “better applications of current antibiotics are urgently needed” [[33]Diel R. Ringshausen F. Richter E. Welker L. Schmitz J. Nienhaus A. Microbiological and clinical outcomes of treating non-Mycobacterium avium complex nontuberculous mycobacterial pulmonary disease: a systematic review and meta-analysis.Chest. 2017; 152: 120-142Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar,[34]Novosad S.A. Beekmann S.E. Polgreen P.M. Mackey K. Winthrop K.L. MaS Team Treatment of Mycobacterium abscessus infection.Emerg Infect Dis. 2016; 22: 511-514Google Scholar]. Yet, patient reported outcome (PRO) questionnaires for CF (e.g. CFQ-R), are influenced by many aspects of the condition and may introduce significant variability into trial results. Infections with NTM such as M. abscessus occur infrequently, so to conduct a large enough trial to have meaningful endpoints, multiple centres must be engaged to recruit the required patient numbers, significantly increasing cost. Furthermore, these studies are usually performed on patients refractory to standard therapy, adding to the challenge of demonstrating the benefit of new drugs. The difficulties in achieving endpoints has seen the failure of both dry powder (Bayer) and liposomal (Aradigm) inhaled ciprofloxacin to achieve regulatory authority (FDA) approval, despite reasonably good evidence of efficacy in reducing exacerbations of bronchiectasis associated with Pseudomonas aeruginosa. This outcome may have impacted on the financial viability of Aradigm which has filed for bankruptcy in 2019. In fact, the development of new antibiotics in general, particularly for ‘super bugs’ is fraught with peril. Whilst we want Pharma to develop new antimicrobials, we are also keen to save and or protect such new agents from indiscriminate use and may in turn contribute to poor return and loss of viability to the companies involved [[35]Call C. Achaogen bankruptcy raises worry over antibiotic pipeline. Center for Infectious Disease Research and Policy, 2019http://www.cidrap.umn.edu/news-perspective/2019/04/achaogen-bankruptcy-raises-worry-over-antibiotic-pipelineGoogle Scholar,[36]Commission USSaE. Tetraphase Pharmaceuticals, Inc Annual report. 2019 11th August.https://ir.tphase.com/static-files/374bfa71-774b-4b95-9c15-116ca7cc7da8Google Scholar]. These considerable challenges have resulted in very few clinical trials being performed in NTM disease, leaving an urgent vacuum in clinical management evidence. For NTM however, the duration of therapy is prolonged, and there is a significant rate of reinfection (as high as 40%) [[37]Wallace J.R.J. Brown-Elliott B.A. McNulty S. Philley J.V. Killingley J. Wilson R.W. et al.Macrolide/azalide therapy for nodular/bronchiectatic: Mycobacterium avium complex lung disease.Chest J. 2014; 146: 276-282Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar]. It has been estimated 13–24% [[38]Olivier K.N. Weber D.J. Wallace Jr., R.J. Faiz A.R. Lee J.-H. Zhang Y. et al.Nontuberculous mycobacteria: I: multicenter prevalence study in cystic fibrosis.Am J Respir Crit Care Med. 2003; 167: 828-834Crossref PubMed Scopus (464) Google Scholar] of patients with CF have NTM (estimated at 5500 patients in the US, and 12,000 world-wide [[39]Qvist T. Pressler T. Noiby N. Katzenstein T. Shifting paradigms of nontuberculous mycobacteria in cystic fibrosis.Respir Res. 2014; 15: 41):1-6Google Scholar] and the numbers appear to be rising [[1]Floto R.A. Haworth C.S. The growing threat of nontuberculous mycobacteria in CF.J Cystic Fibrosis. 2015; 14: 1-2Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar]. The prevalence of NTM in non-CF patients is estimated at 100,000 to 150,000 patients in the US alone [[40]Johnson M. Odell J. Nontuberculous mycobacterial pulmonary infections.J Thor Dis. 2014; 6: 210-220PubMed Google Scholar]. There is clearly a potential market. With the success of recent clinical trials utilising Arikayce, the work of Banaschewski and his team and others in the field, we as clinicians can hope that there is a light emerging in the tunnel, that will deliver for our patients with these serious infections.