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Comment |
1 Menzies Research Institute, Hobart, Tasmania, Australia
2 The Prince Charles Hospital, Chermside, Brisbane, Queensland, Australia
Correspondence
D. W. Reid
(d.e.c.reid{at}utas.edu.au)
The recent report by Bartholdson et al. (2008)
demonstrating production of large amounts of exopolysaccharide (EPS) by organisms of the Burkholderia cepacia complex (Bcc), which changed the phenotype from non-mucoid to mucoid when the bacteria were exposed in vitro to a variety of sugar alcohols including mannitol, fructose and sucrose, raises a worrying scenario. Mannitol as an inhaled therapy appears to increase the hydration of airway secretions and thus promote airway clearance, with demonstrated improvements in lung function (Jaques et al., 2008; Minasian et al., 2007). As Bartholdson and colleagues highlight, cystic fibrosis (CF) patients infected with Bcc have been excluded from the clinical trials of mannitol in order not to confound results, given the potential adverse impact of some of these strains on lung function decline. In Australia, 4.1 % of all CF individuals are infected with Bcc, but the prevalence rises with increasing age (Australian CF Data Registry Report 2005). Similar or higher prevalence of Bcc infection has been reported from Europe, the USA and Canada (Lambiase et al., 2006). The obvious concern is that despite the findings of Bartholdson and colleagues, mannitol will be prescribed in Bcc-infected patients. The large multi-centre studies of hypertonic saline (Elkins et al., 2006) and azithromycin (Saiman et al., 2003) have also excluded patients with Bcc infection; however, these treatments are now frequently prescribed in this patient population (unpublished observations). Interestingly, strains of the more virulent ET12 strain of Burkholderia cenocepacia did not produce EPS following growth on mannitol, and the critical determinant here appears to be the bce gene cluster, with ET12 strains possessing an 11 bp deletion that prevented bce upregulation by mannitol and thus EPS production. Paradoxically therefore, mannitol may not be of great concern when administered to patients infected with the ET12 strain, but may have adverse consequences when used in the setting of what are generally considered less virulent strains.
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). Assessment of sugar moieties has not been undertaken in CF sputum, but levels of fructose and other sugar alcohols are elevated in the serum of patients with diabetes and are likely to be similarly increased in airway secretions in patients with CFRD, providing a favourable substrate for bacterial growth (Kawasaki et al., 2002). The findings of Bartholdson and colleagues would also suggest that the lungs of patients with CFRD may promote bacterial virulence, i.e. EPS production by Bcc. Careful analysis of the impact of CFRD on CF patients with Bcc infection is required but will need international collaboration to ensure sufficient patient numbers to provide statistical power. New therapies such as mannitol will require close scrutiny in patients with Bcc infection, although the evidence indicates that this therapy will be of benefit in those infected with P. aeruginosa, who constitute the vast majority of the CF population.
REFERENCES
Bartholdson, S. J., Brown, A. R., Mewburn, B. R., Clarke, D. J., Fry, S. C., Campopiano, D. J. & Govan, J. R. (2008). Plant host and sugar alcohol induced exopolysaccharide biosynthesis in the Burkholderia cepacia complex. Microbiology 154, 2513–2521.
Elkins, M. R., Robinson, M., Rose, B. R., Harbour, C., Moriarty, C. P., Marks, G. B., Belousova, E. G., Xuan, W. & Bye, P. T. (2006). A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. N Engl J Med 354, 229–240.
Jaques, A., Daviskas, E., Turton, J. A., McKay, K., Cooper, P., Stirling, R. G., Robertson, C. F., Bye, P. T., Lesouëf, P. N. & other authors (2008). Inhaled mannitol improves lung function in cystic fibrosis. Chest 133, 1388–1396.[CrossRef][Medline]
Kawasaki, T., Akanuma, H. & Yamanouchi, T. (2002). Increased fructose concentrations in blood and urine in patients with diabetes. Diabetes Care 25, 353–357.
Lambiase, A., Raia, V., Del Pezzo, M., Sepe, A., Carnovale, V. & Rossano, F. (2006). Microbiology of airway disease in a cohort of patients with cystic fibrosis. BMC Infect Dis 6, 4[CrossRef][Medline]
Lanng, S., Thorsteinsson, B., Nerup, J. & Koch, C. (1994). Diabetes mellitus in cystic fibrosis: effect of insulin therapy on lung function and infections. Acta Paediatr 83, 849–853.[Medline]
Minasian, C. C., Wallis, C. & Bush, A. (2007). Mannitol as a mucolytic in cystic fibrosis. J R Soc Med 100 (Suppl. 47), 53–56.[Medline]
Saiman, L., Marshall, B. C., Mayer-Hamblett, N., Burns, J. L., Quittner, A. L., Cibene, D A., Coquillette, S., Fieberg, A. Y., Accurso, F. J. & other authors (2003). Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA 290, 1749–1756.
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