**14. Non-tuberculous Mycobacteria (NTM)**

**12.** *Staphylococcus aureus*

12 Cystic Fibrosis in the Light of New Research

**13.** *Burkholderia cepacia* **complex**

Amongst the earliest pathogens to become clinically prominent in the life of patients with CF is *Staphylococcus Aureus* (SA) [58]. Its prevalence globally is 44%–56% (2008) in its methicillin sensitive form (MSSA) and 8%–23% for methicillin resistant strains (MRSA). The difficulty in accurately establishing the relevance of SA as a pathogen in CF may lie in the complexity involved in characterising the specific virulence of the strains involved. MSSA, *Small colony variant MSSA* (SCV-MSSA) and MRSA (both community acquired-MRSA and healthcare associated MRSA) all differ in resistance patterns and apparent virulence. A study by Hoffman et al. in 2006 [59] suggested that co-colonisation with MSSA and PA favoured the formation of SCV-MSSA. Subsequent work by Besier et al. [60] associated colonisation with SCV-MSSA with worse lung function, more PA co-infection and more antibiotic resistance than those with MSSA. This is especially telling when colonisation with PA and SA is not uncommon. During a 1990s US-based clinical trial [61] an analysis of baseline sputum found 43% of participants to culture both PA and SA. Current evidence suggest that patients culturing MRSA have worse lung function and require more antibiotics than those with MSSA [62] and that PA/MRSA cocolonisation is associated with more pronounced decline in lung function than PA/MSSA cocolonisation [63]. Controversy still exists surrounding the long established practice of prescribing prophylactic antimicrobials with activity against MSSA. Although studies have suggested reduced cough and less culture positivity in the setting of prophylaxis, no clear benefits in terms of outcomes have been observed. Furthermore, several studies have pointed to increased and earlier incidence of PA culture in patients undergoing MSSA suppression therapy [64]. Whilst guidelines published by international bodies vary on their recommenda‐ tion regarding chronic anti-staphylococcal use, a recent Cochrane review found no convincing evidence for treatment [65] and reiterated concerns around the increase in PA colonisation.

Long mistaken for a *Pseudomonas*, *Burkholderia* species were identified more accurately in the 1980s and 1990s as diagnostic techniques improved. Now recognised as perhaps the most virulent pathogens in CF, they present a major treatment challenge. The *Burkholderia Cepacia Complex* (BCC) is comprised of at least 17 distinct species of gram-negative bacteria. Termed Genomovars, these species vary in prevalence and apparent virulence. The most common BCC strains identified are *B.Cenocepacia* and *B.Multivorans*. Evidence from 2002 revealed a four-fold mortality risk in patients colonised with epidemic *B.Cenocepacia*, associated with a more rapid rate of lung function decline versus others (FEV1 -1.9% vs. -0.3% per annum) [66]. Further data from 2004 showed *B.Cenocepacia* was associated with a statistically significant higher rate of lung function decline (-140 ml/year vs. -32 ml/year (p=0.01)) and reduction in BMI when compared to PA and *B.Multivorans* [67]. Whilst evidence is mounting that specific BCC genomovars have a hierarchy of virulence with *B.Cenocepacia* associated with the highest morbidity, it is worth noting that progressive disease can be caused by a multitude of strains. "*Cepacia Syndrome*", a constellation of sepsis, fevers, and leucocytosis and fulminant decline

A 2013 study by Bryant et al. [71] demonstrating patient to patient transmission of *Mycobac‐ terium Abscessus* (*subspecies Massiliense*) in a CF centre re-focused attention on the clinical management and implications of NTM colonisation. Prevalence (6%-14%) of NTM organisms is variable and changing with time [72] and patient phenotype appears to dictate colonisation with younger, more malnourished patients with more severe genotypes culturing more *Mycobacterium Abscessus Complex* (MBASC) organisms than *Mycobacterium Avium Complex* (MAC) [73, 74]. Recurrent NTM culture positive status has been shown to be associated with progression of HRCT changes [75], however, despite these findings, statistical evidence indicating worse outcomes in pulmonary function or mortality is lacking. With the employ‐ ment of prophylactic macrolide treatment for reduction of exacerbations, significant concerns were raised regarding the possibility of developing macrolide resistance in colonising NTM species; hence, NTM culture positivity is a contraindication to macrolide prophylaxis. Longterm macrolide use may, however, have a protective effect in reducing incidence of NTM culture positivity as highlighted by Coolen et al. in 2015 [76]. This finding could have a significant impact on prognosis and treatment options, as NTM colonisation is still considered a contraindication to transplant in some centres despite growing evidence that outcomes posttransplant in this cohort are acceptable [77].
