Non-tuberculous mycobacteria and Cystic fibrosis
The Leeds Method of Management. April, 2008. Nontuberculous mycobacteria and Cystic fibrosis [online]. Leeds Regional Adult and Paediatric Cystic Fibrosis Units, St James's University Hospital, Leeds, UK. Available from http://www.cysticfibrosismedicine.com
With the widespread use of antibiotics and dramatic improvement in patients survival, newer organisms, such as Stenotrophomonas maltophilia (Denton et al, 1996; Denton et al, 1998; Talmaciu et al, 2000; Krzewinski et al, 2001), Achromobacter xylosoxidans (Dunne & Maisch, 1995; Krzewinski et al, 2001; Tan et al, 2002) and nontuberculous mycobacteria (Tomashefski et al, 1996; Torrens et al, 1998; Olivier et al, 2003) are becoming more widespread. The reasons for their emergence are complex but may relate to the selective pressure exerted by repeated exposure to antibiotic therapy, improved laboratory isolation techniques and enhanced reporting. All may be associated with either simple colonisation or respiratory exacerbations in those persistently colonised with large numbers of these organisms.
The prevalence of nontuberculous mycobacteria (NTMs) in the Adult CF Unit in Leeds was 3.8% in 1998 (Torrens et al, 1998). More recent studies suggest that this might now be higher. Pierre-Audigier et al reported a prevalence of 8.1% in three French CF Centres (Pierre-Audigier et al, 2005) and Olivier et al reported an overall prevalence of 13% from 21 CF Centres in the USA (Olivier et al, 2003). Prevelance is age-related with lower rates seen in children (Esther et al, 2005; Pierre-Audigier et al, 2005). The NTMs associated with CF can be broadly separated into three groupings: Mycobacterium avium complex; rapid growers consisting of Mycobacterium abscessus, Mycobacterium chelonae and Mycobacterium fortuitum; and others. The most commonly isolated species in CF are M. avium complex and the rapid growers, especially M. abscessus (Torrens et al, 1998; Olivier et al, 2003; Esther et al, 2005; Pierre-Audigier et al, 2005). The source of NTMs for persons with CF remains elusive and there is no evidence of patient-to-patient spread (Sermet-Gaudelus et al, 2003).
Clinical significance of NTM in cystic fibrosis
The clinical significance of NTMs varies from patient to patient. Assessment can be aided by the use of American Thoracic Society criteria (American Thoracic Society, 1997), which are based on clinical, microbiological and radiological parameters, although these have not been specifically validated for CF. M. abscessus is the species most closely associated with clinical significance (Pierre-Audigier et al, 2005) and infection may become chronic and lifelong. It has been suggested that infection with atypical mycobacteria should not be an exclusion criterion for lung transplantation. Although 14% of people with CF undergoing lung transplantation were positive for atypical mycobacteria in one study, the prevalence of post-transplant invasive mycobacterial infection was low (3.4%) and was associated entirely with M. abscessus (Charlermskulrat et al, 2006). The latter should be seen as a strong relative, if not absolute, contraindication to lung transplant. Disseminated pulmonary infection may occur post transplant despite aggressive therapy (Taylor & Palmer, 2006).
|Figure 1. Mycobacterium. avium and granuloma - biopsy proven|
|Figure 2. Mycobacterium. chelonae and granuloma found on lung biopsy following a pneumothorax|
|Figure 3. Acute deterioration due to Mycobacterium abscessus which responded to intense therapy|
It is not clear what the optimum treatment regimens for NTMs are and much of the evidence is provided by in-vitro rather than in-vivo studies. They are often resistant to most of the antibiotics commonly used to treat other infections in CF and to standard treatments used to treat Mycobacterium tuberculosis. Most isolates of M. avium appear susceptible to macrolides, such as clarithromycin and azithromycin, on initial isolation (Heifets, 1996) and these are most effective when combined with two or three other drugs, such as rifampicin and ethambutol (Yajko et al, 1996; Field et al, 2004). The most active drug against rapid growers is amikacin, although other agents with in vitro activity include cefoxitin, clarithromycin, imipenem and linezolid (Brown-Elliot & Wallace, 2002; Yang et al, 2003). M abscessus is more resistant than other members of the group. Tigecycline has in vitro activity against rapid growers, but not against M. avium (Wallace et al, 2002). There is some evidence that patients with defects in immunological pathways, particularly those associated with interferon, may be more susceptible to infection with NTMs. The use of aerosolised interferon has been anecdotally associated with successful treatment of M. abscessus infection in CF (Hallstrand et al, 2004). In Leeds we have developed a treatment algorithm based on the currently available data. Further studies are needed to ascertain the optimum management of NTMs in CF.
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