Department of Pathological Sciences, University of Manchester, 2nd Floor Clinical Sciences Building, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
An important recent development in CF patients has been the emergence of infection by antibiotic resistant Burkholderia cepacia, which is frequently associated with rapid clinical deterioration and sometimes bacteraemia.3 Antibiotic treatment remains unsatisfactory for chronic infections, although it relieves the symptoms of acute pulmonary exacerbation and thus acts as a palliative and not a cure.
Rifampicin is not usually used for the treatment of B. cepacia in CF patients, but rifampicin in combination with other anti-pseudomonal antibiotics was synergic in vitro against B. cepacia isolated from the sputa of CF patients.4 Doxycycline is a semi-synthetically produced substance (6-deoxy-hydroxytetracycline) with similar activity to tetracycline but improved pharmacokinetic properties that permit od dosing, increasing its convenience in clinical use. We know of no reports of its use in the treatment of B. cepacia infections.
Lactoferrin serves as a non-specific antimicrobial agent, which protects against systemic and secretory surface infections.5 Its presence increases the susceptibility of Salmonella typhimurium to rifampicin, ampicillin, ciprofloxacin, erythromycin and chloramphenicol,6 and Escherichia coli to rifampicin.7 Lactoferrin concentration increases during bacterial infection and is found in a very high concentration (0.9 g/L) in the sputa of CF patients colonized with P. aeruginosa.8 This high concentration of lactoferrin increases the susceptiblity of P. aeruginosa9 to rifampicin and chloramphenicol. In view of these findings and the apparent benefit conferred by doxycycline therapy of CF patients with P. aeruginosa infection, we have investigated the effect of lactoferrin at the concentration found in CF sputum on MICs and MBCs of doxycycline for B. cepaciaand P. aeruginosa, and of rifampicin for B. cepacia.
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The rifampicin and doxycycline powders used (Sigma Ltd, Poole, UK) were 95% and 98% potent, respectively. Other materials and methods were those described previously,9 using the broth microdilution method,10 modified in that an equal volume of organism suspension was added to each working dilution of antibiotic. The inoculum was diluted to give a final concentration in the wells of 104105/mL. Antibiotic-free controls with and without lactoferrin were included. Human recombinant lactoferrin from Aspergillus awamori was provided by Agennix Inc., Houston, TX, USA. Statistical analysis was by MannWhitney U test (two tailed).
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Our study arose in part from the clinical impression of benefit conferred by doxycycline therapy in CF patients with respiratory infection by P. aeruginosa. The in-vitro effect of lactoferrin in reducing the MICs of doxycycline for P. aeruginosa points to a possible basis for the impression, although MICs of our strains in the presence of lactoferrin were still quite high. The far greater effect on MICs of doxycycline for B. cepacia, an important pathogen for adult CF patients, points to a potentially important new approach to treatment and the necessity for a controlled clinical trial.
The effect of lactoferrin on susceptibility to rifampicin, similar to that already described for P. aeruginosa9 points to its potential for treating B. cepacia in adults with CF. If the results of controlled clinical trials are found to support our findings, this would suggest a need to revise sensitivity tests to match them to in-vivo systems by the addition of lactoferrin to the medium.
![]() |
Acknowledgments |
---|
![]() |
Notes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2 . Korvick, J. A., Peacock, J. E., Muder, R. R., Wheeler, R. R. & Yu, V. L. (1992). Addition of rifampicin to antibiotic therapy for Pseudomonas aeruginosa bacteraemia: prospective trial using the zelen protocol. Antimicrobial Agents and Chemotherapy 36,620 5.[Abstract]
3 . Govan, J. R. W., Hughes, J. E. & Vandame P. (1996). Burkholderia cepacia: medical, taxonomic and ecological issues. Journal of Medical Microbiology45 , 395407.[Abstract]
4 . Kumar, A., Wofford-McQueen, R. & Gordon, C. (1989). Ciprofloxacin, imipenem and rifampicin: in vitro synergy of two and three drug combinations against Pseudomonas cepacia. Journal of Antimicrobial Chemotherapy 23, 8315.[Abstract]
5 . Bullen, J. J. (1981). The significance of iron in infection. Reviews of Infectious Diseases 3, 112738.[ISI][Medline]
6 . Naidu, A. S. & Arnold, R. R. (1994). Lactoferrin interaction with Salmonellae potentiates antibiotic susceptibility in vitro. Diagnostic Microbiology and Infectious Diseases 20, 6975.[ISI][Medline]
7 . Ellison, R. T., La Force, M., Ghiel, T. J., Boose, D. S. & Dunn, B. E. (1990). Lactoferrin and transferrin damage of the Gram-negative outer membrane is modulated by Ca2+ and Mg2+. Journal of General Microbiology 136, 143746.[ISI][Medline]
8 . Jacquot, J., Tournier, J. M., Carmona, T. G., Puchelle, E., Chazalette, J. P. & Sadoul, E. (1983). Proteines des secretions bronchiques dans la mucoviscidose. Role de l'infection. Bulletin Europeen de Physiopathologie Respiratoire 19, 4538.[ISI][Medline]
9 . Fowler, C. E., Soothill, J. S. & Oakes, L. (1997). MICs of rifampicin and chloramphenicol for mucoid Pseudomonas aeruginosa strains are lower when human lactoferrin is present. Journal of Antimicrobial Chemotherapy 40, 8779.[Abstract]
10 . Working Party of the British Society for Antimicrobial Chemotherapy. (1991). A guide to sensitivity testing. Journal of Antimicrobial Chemotherapy 27Suppl. D.
Received 19 November 1998; returned 16 March 1999; revised 29 March 1999; accepted 27 April 1999