B. cepacia: What is it and Why is it a Concern?

Hospitals and Pharmaceutical Plants on the Prowl for this Uninvited Guest

Burkholderia cepacia has been in the news...again!

Even though this pathogen is not a newcomer (one can easily findpapers from the 1990s discussing its dangers), it continues to wreak havoc in pharmaceutical plants (1). Less than two years ago, two separate batches of oral solid medicine were found to be contaminated by B. cepacia (2,3). The year before,a manufacturer issued a Class I recall for saline flush IV syringes suspected to be responsible for B. cepacia bloodstream infections (4). A quick Web search shows these are not isolated cases. B. cepacia is a major contaminant in both sterile and nonsterile products. A review of U.S. FDA recall data from January 2012 to July 2012 found that 39% of contamination cases in non sterile products were due to the presence of B. cepacia (5).

Before continuing, one might wonder, what is B. cepacia? B. cepacia is actually the name given to a group of Gram negative aerobic rod-shaped bacteria (Burkholderia Cepacia Complex or BCC). Despite living mainly in aerobic environments, those bacteria can survive in hypoxic conditions and possess the ability to grow in low nutrient media as well. This microorganism is generally harmless to healthy individuals but acts as an opportunistic pathogen, presenting a potentially fatal danger to immunocompromised patients. A recent study performed in Severance Hospital at Yosei University College of Medicine in Korea found a mortality rate of 41% among individuals suffering of B. cepacia-induced bacteremia (6). This is a problematic issue as this pathogen is quite proficient at reaching sick individuals through two main channels: hospital fluids and contaminated pharmaceutical products (7).

A Hardy, Vicious Microorganism

There is another feature of B. cepacia worth to highlight, and this is its proficiency at developing a biofilm matrix. Biofilm forming organisms feature a wide range of bacteria, including mainly Gram negative but also Gram positive pathogens (8,9). These microorganisms are generally quite hardy since the biofilm acts as a net that stops antibiotics from penetrating into the actual bacterial cell, exposing only the planktonic cells outside the matrix. (10). For this reason, bacteria communities that form biofilms show a higher than average resistance to antibiotics, stress and many other conditions that are usually detrimental to cells (11). All in all, it makes dealing with biofilm-forming bacteria difficult, especially those inside an individual’s body.

A famous example of a biofilm-related disease would be cystic fibrosis, which is mainly caused by Pseudomonas aeruginosa—a bacterium with a long, well-known association with B. cepacia (in fact, B. cepacia was initially known as Pseudomonas cepacia) (12). Even though changes in antibiotic administration patterns (like alternate antibiotic cycles or combined antibiotics administration) can significantly reduce its mortality, many biofilm infections are considered chronic, as a complete elimination of the pathogen from the host is very difficult. This, coupled with the great difficulty in detecting it via conventional methods, makes it a really unpleasant microorganism to deal with. Naturally,limiting its chances to reach hospitals is vital to avoid a problem that presents huge human and economic costs.

Manufacturers Fight B. cepacia

But it is not only hospitals that are involved in this crusade against B. cepacia. Pharmaceutical companies have also a huge interest in eradicating this pathogen from their facilities, as its very presence forces production to stop, risking potential loss of clients, and even causing severe economic losses in some cases. As mentioned before, fighting a biofilm-inducing bacterium inside a human host can be a complicated task. Yet eradicating its presence in a plant’s water systems might not be as difficult. Fortunately, the industrial environment allows for use of more aggressive methods and chemicals. Some new products have been appearing on the market, offering potential solutions that are more efficient solutions than conventional bactericides. Many scientific teams are focusing on new approaches to eradicate B.cepacia (13). Still, present solutions have, so far, failed at eliminating B. cepacia completely from both infected humans and industrial water conducts.

Two-Front Approach to B. cepacia

Risk management of B. cepacia contamination can be tackled from two different perspectives. There is the hospital approach, which focuses on good hygiene and patient segregation based on their microbiological status, and there is the industrial approach, which is based on detecting this microorganism efficiently enough to avoid contaminated products reaching the market.

Detecting B. cepacia presence is a hard task. B. cepacia is a bacterium that usually presents slow growth and many times remains undetected until it is too late (14,15). USP considered this matter critical enough as to dedicate a general chapter—which is currently undergoing an In-Process Revision—featuring tests for growth promoting, indicative and inhibitory properties of the media and a list of recommended media for the tests, and clues for the interpretation of possible B. cepacia colonies (16). In addition, some newer techniques like real-time polymerase chain reaction are being used in order to speed up the detection process (17). It is also true, however, that these techniques, while being quicker than the traditional methods, are still relatively time consuming compared to others.

The development of an in situ media-independent device to detect B. cepacia in water (something similar to point-of-care devices in hospitals) could mean a big step toward better, quicker detection. Meanwhile, detection remains problematic. In order to lower the risks of B. cepacia spreading to the general public, it is recommendable to invest money on efficient detection systems for B. cepacia early detection. It is also highly advisable to thoroughly disinfect, especially in cases where B. cepacia or other biofilm-forming bacteria have been spotted.

Knowing the gravity of the situation, it might seem logical to think that B. cepacia should be considered a serious threat and be dealt with properly. In the end, tackling the problem at its source will save many lives and millions for both pharmaceutical plants and hospitals.

Published at PDA Letter (April 2019). Link: https://pda.inloop.com/en/article/114233/b-cepacia-what-is-it-and-why-is-it-a-concern

References

1. Koenig, D. W., Mishra, S. K., and Pierson, D.L. “Removal of Burkholderia cepacia biofilm swith oxidants.” Biofouling 9 (1995): 51-62.
2. Office of Regulatory Affairs. (2017, August 2). Recalls, Market Withdrawals, & Safety Alerts Rugby Laboratories Issues Voluntary Nation-wide Recall of Diocto Liquid and Diocto Syrup Manufactured By PharmaTech, LLC Due to Possible Product Contamination
3. Office of Regulatory Affairs. (2017, August 30). Recalls, Market Withdrawals, & Safety Alerts - Mid Valley Pharmaceutical LLC Issues Voluntary Recall of Doctor Manzanilla Cough& Cold and Doctor Manzanilla Allergy &Decongestant Relief Syrup Due to Potential Contamination with Burkholderia Cepacia.
4. Center for Devices and Radiological Health. (2016, October 4). Medical Device Recalls Nurse Assist Inc. Recalls Normal Saline Flush IV Syringes Due to Possible Burkholderia Cepacia Bloodstream Infections.
5. Ali, M. “Burkholderia Cepacia in Pharmaceutical Industries.” International Journal of Vaccines & Vaccination, 3 (2016)
6. Ku, N. S., et al. “Risk factors for mortality inpatients with Burkholderia cepacia complex bacteraemia.” Scandinavian Journal of Infectious Diseases, 43 (2011): 792-797.
7. Mahenthiralingam, E., et al. “The multifarious, multireplicon Burkholderia cepacia complex.” Nature Reviews Microbiology 3 (2005): 144-156.
8. Schembri, M. A., et al. “An Attractive Surface:Gram-Negative Bacterial Biofilms.” Science Signaling (2002) 132.
9. Abee, T., et al. “Biofilm formation and dispersal in Gram-positive bacteria.” Current Opinion in Biotechnology 22 (2011): 172-179
10. Murphy, M. P., and Caraher, E. “Residence in biofilms allows Burkholderia cepacia complex(Bcc) bacteria to evade the anti-microbial activities of neutrophil-like dHL60 cells.” Pathogens and Disease (2015).
11. Gough, N. R. “Complexity in the Bacterial Community.” Science Signaling (2008).
12. “Identification of the Burkholderia cepacia complex by PCR from isolated cultures or direct analysis of sputum from cystic fibrosis patients in Brazil.” Journal of Cystic Fibrosis (2005): 4
13. Sousa, S. A., et al. “Post-genomic Approaches and Bioinformatics Tools to Advance the Development of Vaccines against Bacteria of the Burkholderia cepacia Complex.” Vaccines 6 (2018).
14. Pope, C. F., et al. “Approaches to measure the fitness of Burkholderia cepacia complex isolates.” Journal of Medical Microbiology, 59 (2010): 679-686.
15. Govan, J. R., et al. “Common Questions About Burkholderia cepacia” UGent.
16. <60> MICROBIOLOGICAL EXAMINA-TION OF NONSTERILE PRODUCTS—TESTS FOR BURKHOLDERIA CEPACIACOMPLEX.” USP Pharmacopeial Forum, Sept. 2018,
17. Lowe, C., et al., “A Quadruplex Real-Time PCR Assay for the Rapid Detection and Differentiation of the Most Relevant Members of the B. pseudomallei Complex: B. mallei, B. pseudomallei, and B. thailandensis.” Plos One 11 (2016).