Antibiotic resistance in Burkholderia cepacia at two regional cystic fibrosis centres in Northern Ireland: is there a need for synergy testing?

John E. Moorea, Mary Crowea, Adrienne Shawa, John McCaughanb, Aileen O. B. Redmondb,* and J. Stuart Elbornc*

a Northern Ireland Public Health Laboratory, Department of Bacteriology, Belfast City Hospital, Belfast BT9 7AD; b Northern Ireland Regional Paediatric Cystic Fibrosis Centre, Royal Belfast Hospital for Sick Children, Grosvenor Road, Belfast; c Northern Ireland Regional Adult Cystic Fibrosis Centre, Belfast City Hospital, Lisburn Road, Belfast BT9 7AB, UK

Sir,

Infection with the Burkholderia cepacia complex (BCC) continues to present both a diagnostic and management challenge in cystic fibrosis (CF). One difficulty associated with the treatment of infections with this organism with antibiotics has been, and remains, the acquisition of antimicrobial resistance. Previously, many centres have reported high levels of resistance against several classes of antibiotics.1,2 To date, there have been limited data reported on the antimicrobial resistance status of BCC in the Northern Ireland CF population, hence it was the aim of this study to examine and report on the susceptibility of wild-type BCC isolates from all infected adults and children to a wide variety of antimicrobial agents. Presently, prevalence rates of BCC within the Northern Ireland CF population are 24/109 (22%) adults, with 21 (88%) of these patients being colonized by B. cepacia genomovar III and the remaining three patients being colonized by B. multivorans.3 Seven children are infected with this organism in a population of 230 (3%), and all of these children have B. cepacia genomovar III. Antimicrobial susceptibility assays were performed on all recent BCC isolates employing a modified Stokes' disc diffusion assay on DST agar (Oxoid Ltd, Basingstoke, UK) supplemented with 5% v/v defibrinated horse blood, with the following antibiotics (µg): ciprofloxacin (5), colistin (10), ceftazidime (30), azlocillin (75), aztreonam (30), imipenem (10), gentamicin (10), tobramycin (10), meropenem (10), amikacin (30), temicillin (30) and piperacillin/tazobactam (110). Antibiotic disc concentrations were similar for adults and children with the exception of colistin, which was 25 µg for testing with children. Susceptibility data are shown in the Table. Overall, the paediatric isolates were more susceptible to several antibiotics than the adult BCC organisms, and this may allow for an opportunity to attempt to eradicate the organism on first isolation from the lung, when the organism is still relatively susceptible. In addition, the B. multivorans isolates were more susceptible in the adult patients than B. cepacia genomovar III isolates. However, it was noted that 81% of the adults were infected with a pan-resistant genomovar III epidemic organism.

With the emergence of pan-resistance in BCC organisms, in particular in B. cepacia genomovar III, clinicians are often compromised in choosing combinations of two or more agents in order to obtain a synergic effect, in the absence of any in vitro synergy data. Previous data from North America, where such synergy testing is available on request, have indicated various combinations with limited activity in vitro.1 In this study, 47% of isolates demonstrated antagonism when a second antibiotic was added, and triple combinations of tobramycin, meropenem and an additional antibiotic were most effective and were bactericidal against 81–93% of isolates tested. However, no data are available to indicate the in vitro efficacy of these combinations against UK isolates. Recently, Mackay et al.4 examined a chequerboard method and time–kill curves to examine antagonism and synergy in seven BCC isolates, and showed synergy by time–kill curve with a combination of rifampicin and ceftazidime, but were unable to demonstrate antagonism in any of the combinations employed.

In conclusion, antimicrobial management of BCC in CF remains a complex problem, and hence some form of synergy testing, especially testing to examine and prevent antagonism, should form a basis to help guide more efficacious combinations of agents used. Development of a UK reference laboratory for antagonism/synergy testing of isolates should be evaluated further to help guide optimal and appropriate therapy in such patients.


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Table. Antibiotic susceptibility in the CF population in Northern Ireland
 
Notes

* Corresponding author. Tel: +44-28-9032-9241 ext. 3119; E-mail: stuart.elborn{at}bch.n-i.nhs.uk Back

References

1 . Aaron, S. D., Ferris, W., Henry, D. A., Speert, D. P. & MacDonald, N. E. (2000). Multiple combination bactericidal antibiotic testing for patients with cystic fibrosis infected with Burkholderia cepacia. American Journal of Respiratory and Critical Care Medicine 161, 1206–12.[Abstract/Free Full Text]

2 . Burns, J. L. & Saiman, L. (1999). Burkholderia cepacia infections in cystic fibrosis. Pediatric Infectious Diseases Journal 18, 155–6.[Medline]

3 . McDowell, A., Dunbar, K., Moore, J. E., Webb, K., Dodd, M., Mahenthiralingam, E. et al. (1999). Speciation of the B. cepacia complex directly from CF sputum. Pediatric Pulmonology 28, Suppl. S19, 271–2.[ISI][Medline]

4 . Mackay, M. L., Milne, K. & Gould, I. M. (2000). Comparison of methods for assessing synergic antibiotic interactions. International Journal of Antimicrobial Agents 15, 125–9.[ISI][Medline]