John E. Moore & J. Stuart Elborn*. Nov, 2003. Burkholderia cepacia and cystic fibrosis [online]. Northern Ireland Public Health Laboratory, * Northern Ireland Regional Adult Cystic Fibrosis Centre, Belfast City Hospital, Northern Ireland, United Kingdom. Available from http://www.cysticfibrosismedicine.com
In the mid 1940's, vegetable growers in New York State became infected by an organism which had been previously known to cause onion bulbs to rot. Following this outbreak, three bacterial isolates were identified in the autumn of 1947 and a fourth in the autumn of 1948. These were given the latin name, "cepacia" meaning "of or like onion" by Walter H. Burkholder, Cornell University, New York, in his report to Phytopathology, accepted for publication on 6 September 1949.
Fifty years on, this organism is now recognised as one of the most important bacterial invaders and colonisers of the lungs of patients with cystic fibrosis (CF). Although first described in 1949, Burkholderia cepacia has been around for a very long time and it is better to think of this complex of organisms, as emerging pathogens in CF. Such emerging pathogens, already present in the environment, advanced from virtual obscurity to notoriety by being given a selective advantage, through changing environmental and social conditions and an opportunity to infect a new and susceptible host population in patients with CF.
Over recent years the nomenclature of this group of organisms has changed. Formerly known as Pseudomonas cepacia or Pseudomonas multivorans [2], the species was moved to the new genus, Burkholderia, in 1992. In 1997, Vandamme and colleagues defined five sub-species types of cepacia, termed "genomovars" or "genomic species". The term "genomovar" is commonly used with this genus to denote species which are phylogenetically distinguishable from each other, but which are phenotypically indistinguishable. Genomovars have specific different genotypes but are not distinguished by the usual biochemical tests carried out in routine microbiology labs. The genomovar becomes a species when a biochemical test allows it to be identified.
There have since been several molecular methods developed to help laboratory characterization of these types [3-6]. Presently, the formerly recognised genomovars of B. cepacia include B. cepacia genomovar I, B. multivorans (formerly genomovar II), B. cenocepacia (formerly genomovar III), B. stabilis (formerly B. cepacia genomovar IV), B. vietnamiensis (formerly B. cepacia genomovar V), B.ambifaria (genomovar VII), B anthina (genomovar VIII) and B. pyrrocinia (genomovar IX). Indeed, with further characterisation of additional strains, this list of genomovars could grow to at least 10 members. Features, such as the presence of the B. cepacia epidemic strain marker (BCESM) [3] and cable pilus genes [8] have been identified as markers of transmissibility in the organism. However, the transmissibility and virulence of this organism is not well understood and there is at present much research addressing these specific issues. Whilst B.cenocepacia and B. multivorans are the most common members of the complex to cause infections and clinical deterioration in patients with cystic fibrosis, all members of the B cepacia complex have been recovered from patients with CF lung disease.
Pathogenesis and transmissibility
Recurrent and chronic respiratory tract infections in patients with cystic fibrosis results in progressive lung damage and is the primary cause of morbidity and mortality. Infections are usually caused by Gram-negative organisms, especially the pseudomonads including Pseudomonas aeruginosa.
B. cepacia, has emerged as a pathogen in patients with CF that may lead to rapid deterioration of lung function. Infection with B. cepacia complex bacteria may be highly transmissible in CF patients and epidemics have been described in a number of CF centres, in the UK, the USA and Canada, depending on the transmissibility characteristics of individual strains [7]. The strain ET12 lineage, the so-called "epidemic" strain, which has been a particularly virulent clone and which has spread internationally from North America to Europe and subsequently within European countries.
There has been considerable confusion over what is meant by the term "epidemic" strain. The term is sometimes used to describe the prevalent clone which has spread within individual CF centres, but which is not necessarily of the ET12 lineage. Overall, only a minority (5-7%) of CF patients are colonised with this organism and in the UK, although there is a higher prevalence in the large CF centres in the North of England (Manchester, Liverpool, Leeds, Newcastle), as well as in centres in Scotland (Edinburgh & Glasgow) and in Northern Ireland, whereas the prevalence is significantly lower in the South and West of England, as well as in Wales.
Once patients acquire an infection with B. cepacia complex bacteria, clinical progression of the disease follows one of three commonly observed patterns, namely (i). no change in lung function and clinical status, (ii). acceleration of decline in pulmonary function and (iii). fatal decline over a relatively short periods. This is sometimes accompanied by septicaemia, which is often referred to as the "cepacia syndrome". At the Northern Ireland CF Adult Centre in Belfast, of 10 B. cepacia complex related deaths since 1996, 3 could be described as being the cepacia syndrome, from a clinic of 110 patients and a B. cepacia complex prevalence rate of approximately 30%. Most patients do demonstrate an accelerated decline in lung function compared to patients with P.aeruginosa or no Gram negative infection [9].
B. cepacia complex has generated considerable anxiety amongst patients with CF and has changed the way in which CF care teams manage their B. cepacia infected patients. Median survival rates decline markedly to approximately 15-19 years with a history of B. cepacia complex infection. Hence, most units in the UK now segregate patients with this infection from all other CF patients. Nine genomovars or different types of the B. cepacia complex (BCC) or group of organisms have been described and early studies from some centres indicate that genomovar II has less clinical impact than genomovar III [10]. In the Liverpool Adult CF Centre 5 patients acquired a new and more virulent strain of B.cepacia complex. This was likely to be due to a genomovar III strain replacing B.multivorans. Presently B.cenocepacia followed by B. multivorans make up the majority of patients infected with BCC, however the other three genomovars i.e., B. cepacia genomovar I, B. stabilis and B. vietnamiensis are also present in the CF population. Some centres now segregate B. multivorans patients from other B. cepacia complex infected patients (eg Belfast and Vancouver) to reduce the potential of cross-infection between patients with B. cepacia.
Early accurate identification of B. cepacia complex bacteria is of critical importance so the patients can be segregated and therefore the potential for further epidemics is reduced. Coupled with this, CF patients should have their sputum checked at least every three months, in order to monitor changes in their sputum microbiology. By taking this aggressive approach in the Belfast Clinic no adults have acquired B.cepacia complex infection in the past 6 years.
BCC organisms present the clinical microbiologist with a diagnostic dilemma, in that there are extremely few and in some cases no phenotypic biochemical or growth-related characterisation tests that reliably distinguish between these organisms. To this end, there have been a variety of different molecular-based characterisation tests to differentiate the five genomovars. Recently, the recA gene has been shown to aid in the differentiation of the genomovars [5, 6]. A number of other factors have led to the emergence of this infection in the CF community. Continued improvements in clinical care due to a managed multidisciplinary approach at CF care centres have improved life expectancy over the last decade. Until then, B. cepacia complex was not commonly seen and other bacterial infections predominated. However with improving antibiotic chemotherapy and the emergence of new anti-infectives, such as colistin (1987), meropenem and more recently TOBI (tobramycin) against Ps. aeruginosa, infections associated with Ps. aeruginosa and other CF respiratory pathogens have become more manageable, thus allowing the relatively antibiotic-resistant B. cepacia complex organisms to emerge as a significant problem in a minority of patients.
Some patients with CF may transiently acquire infections with a known trabsmissible strain of B.cepacia. The CF trust currently recommend a period of at least one year between negative cultures, during which at least 3 different sputum cultures have been taken, before a patient can be declared as having eradicated a B urkholderia species [12].
Management of Burkholderia cepacia
Patients with cystic fibrosis and chronic Burkholderia cepacia complex infection should be managed with the same principals as those with chronic P. aeruginosa. Careful attention to airways clearance, nutrition, bronchodilator therapy, mucolytic therapy etc is very important. The treatment of acute exacerbations in patients with Burkholderia cepacia complex infection is more problematic. Burkholderia cepacia is almost always multiply resistant to anti-pseudomonal and other antibiotics. However, a number of studies have demonstrated that in spite of this there is frequently a reasonable response to antibiotic combinations. This may be due to synergistic eradicative combinations or due to antibiotics affecting the expression of virulence factors or having anti-inflammatory effects independent of bacterial killing. In a recent study examining the potential for combinations to have activity against Burkholderia cepacia complex, combinations containing Meropenem appeared to be the most advantageous. There are some concerns that combinations particularly of b-lactam based antibiotics can be antagonistic and so methods to assess potential synergy are likely to useful in the future. Drugs such as Chloramphenicol and co-trimoxazole and Tetracyclines can also be valuable in the management of Burkholderia cepacia complex infection in combination. Patients with stable B.cepacia complex do not seem to have more frequent exacerbations compared to patients with P.aeruginosa. The CF community should also be aware of potential hazards to patient welfare of the introduction of this organism for agricultural and bioremediation purposes. These organisms have the ability to degrade numerous organic compounds, which otherwise would present additional chemical environmental hazards. However, careful consideration should be given to the potential for transmission of these organisms to the CF population [10].
Demographic, social and behavioral changes have been important factors in the emergence of B. cepacia complex infection in the CF population. For B. cepacia complex, the highly transmissible nature of certain strains may allow this organism to take advantage of human behaviour. The role of behavioral science in the effort to minimize the spread of this infection from one CF patient to the next cannot be overstated. Mass transportation, mainly through air-travel, allows trans- and inter-continental spread of pan-resistant pathogens from one patient population to another, for instance, aiding the spread of B. cepacia complex from summer camps in Canada to other regions in the world. Once established in a centre, it is very difficult to totally eradicate the imported bacterium. Minimising the risk of transmission of this organism from one individual to another requires a multifactorial approach. The polymerase chain reaction [PCR] has allowed for earlier detection of this organism in the clinical progression of the infection, which may allow for earlier and more aggressive intervention with appropriate antibiotics. In addition, such molecular diagnostic approaches may help by giving direction to segregation policies, thus minimising transmission in both the in-patient and the out-patient setting. Most importantly perhaps is vigilance on the part of the CF patient to adhere to infection control practices. Although tedious and socially difficult to maintain properly, these practices do work. Such an approach has worked for other infectious diseases such as HIV/AIDS and even though there is no effective vaccine, HIV is almost entirely preventable. However, reducing the risk of HIV infection requires important changes in lifestyle and behaviour, as does reducing the risk of B. cepacia infection in CF patients. Recently, the UK Cystic Fibrosis Trust has published the findings of its Infection Control Committee Review relating to B. cepacia complex. These guidelines indicate how best to help prevent the spread of this bacterium from person-to-person. They are based on risk assessment models of various everyday social activities and advise the non-cepacia infected patient on how to avoid acquisition, as well as indicating how responsible the cepacia-positive CF patient should act. For instance, Children's CF Holiday camps are not recommended and likewise CF Trust Caravan Holidays have been stopped due to the potential for the spread of transmissible and virulent organisms from patient-to-patient. Also, current UK, US and Canadian advice is to discourage B. cepacia complex positive patients from attending CF meetings and conferences due to the potential for transmission of these organism. E-mail the CF Trust Office (enquiries@cftrust.org.uk) for further information and a copy of these guidelines.
It is our view that B. cepacia complex will continue to be a problem pathogen in CF. The host-environmental organism interaction is impossible to eliminate, in terms of absolute control, however the risk may be mitigated through awareness in CF patients of where the risks of acquistion lie.
The incidence in CF patients will probably decline provided that
(i). patients comply with important infection control policies in managed CF care centres, which are designed to prevent the spread of this organism, both on an in-patient and out-patient setting,
(ii). there is continued awareness of acquistion risks of B. cepacia by CF patients and adjustment to behaviour to minimise the risk of becoming colonised and infected with this organism and
(iii). CF centres have access to quality microbiology services and Reference Laboratories, to help manage optimum antibiotic regimens and direct appropriate segregation and infection control policies.
For more details see CF (UK) Trust antibiotic consensus section
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Modified with permission from of the PHLS Communicablele Disease Surveillance Centre ©PHLS from Moore JE, Elborn JS. Burkholderia cepacia and CF - 50 years on. Comm Dis and Public Health 2001;4:114-116.
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