“We have a patient with an infective exacerbation of their cystic fibrosis with Burkholderia multivorans but she is allergic to Ceftazidime and Meropenem and gets bad gastrointestinal symptoms with tetracyclines. What do you think?” asked the Respiratory Consultant.
I really like these types of MDTs when I have to scratch my head and try to work out a solution but this one was a bit of a puzzler. I know Ceftazidime and Meropenem are often used to treat infections with Burkholderia spp. and that Minocycline is also an option, but what to do when these can’t be used? I had to admit I didn’t know for sure and that I would have to go and look at the literature and get back to them. So off I went to consultant the “Interweb”.
Burkholderia cepacia complex (Bcc) is a group of related bacteria which are found in soil and water throughout the world (not an abbreviation for “blind carbon copy” as in e-mails!!). Bcc are non-lactose fermenting Gram-negative bacilli. Many people who “grow their own” will have seen Bcc in action as B. cepacia, as it is a cause of onion rot which sours the skin of onions. However, in humans Bcc causes opportunistic infections, principally in patients with cystic fibrosis (CF) and the rarer chronic granulomatous disease.
Members of the Bcc include:
- B. cepacia
- B. multivorans
- B. cenocepacia
- B. stabilis
- B. vietnamiensis
- B. dolosa
- B. ambifaria
- B. anthinia
- B. pyrrocinia
Bcc is highly resistant to many antibiotics due to a number of mechanisms:
- Bcc lack binding sites on their cell membranes for aminoglycosides (Gentamicin, Tobramycin, Amikacin) as well as Polymyxin B (Colistin).
- Bcc lack porins (barrel shaped protein pores) in their outer membranes which when combined with chromosomal beta-lactamases leads to resistance to many of the available beta-lactams (Piptazobactam, Imipenem, Meropenem)
- Bcc can contain efflux pumps that remove antibiotics from inside the bacterium causing resistance to tetracyclines (Tetracycline, Doxycycline), fluoroquinolones (Ciprofloxacin, Levofloxacin) and Chloramphenicol
The main theory as to why it becomes a problem in CF is that the combination of an already damaged lung plus multiple courses of antibiotics, changes the respiratory flora of the CF patient to contain bacteria resistant to the high levels of antibiotics they have been exposed to. There is a pattern to the change of flora in CF patients over time, the speed of which is dependent primarily on compliance with treatment, especially physiotherapy. A typical pattern might look like this:
- Normal respiratory flora – infection treated with Amoxicillin OR Clarithromycin selects out:
- Meticillin-sensitive Staphylococcus aureus – infection treated with Flucloxacillin OR Clarithromycin selects out:
- Meticillin-resistant Staphylococcus aureus – infection treated with Doxycycline OR Teicoplanin selects out
- Antibiotic sensitive Pseudomonas aeruginosa – infection treated with Ceftazidime OR Ciprofloxacin selects out
- Antibiotic resistant Pseudomonas aeruginosa – infection treated with Meropenem PLUS Tobramycin OR Colistin selects out
- Burkholderia cepacia complex
It is easy to see how the patients Bcc might therefore be resistant to many of the antibiotics that have been given before! It is not the patient’s exposure to rotten onions, even though my wife (a “grow your own” guru) still insists we eat the leftover “good bits” of ours!
What is the significance of Bcc infection?
In the context of CF the most important members of the Bcc are B. cenocepacia and B. multivorans. Chronic infection with Bcc in CF is associated with increased morbidity and a shortened life expectancy, and this is especially true following lung transplant surgery. The one year survival post-transplant for CF is only 67% for Bcc infected patients compared to 92% for non-Bcc infected patients, especially if the Bcc is B. cenocepacia. In the past (when my wife was a respiratory physiotherapist rather than a “grow your own” guru!) the survival was so poor that infection with B. cenocepacia was an absolute contraindication to lung transplant; it was a death sentence.
B. multivorans is not as virulent as B. cenocepacia and doesn’t carry quite as high risk following lung transplantation however it is still a cause of morbidity and mortality. Nowadays with improved surgical techniques and aggressive antibiotic therapy Bcc infection is only a relative contraindication; it is considered but on its own wouldn’t stop the transplant taking place.
Another important impact of Bcc infection in CF is that there is a high rate of person-to-person or person-to-environment-to-person transmission. It has major implications for infection control on a CF unit. This means that CF patients with Bcc are managed separately from other CF patients. They do not come to the same clinics, they do not get admitted to normal CF wards and when they have been in hospital there needs to be extensive cleaning of the environment before another CF patient is admitted. This situation runs the risk of ostracising CF patients with Bcc; it is important to ensure that these patients still receive the high levels of specialist care, even if they can’t be admitted to specialist units.
So how is this “scary” bacterium treated?
This is where it gets really difficult. To start with there are two Cochrane systematic reviews into the treatment of Bcc in CF. Basically Cochrane reviews look at all of the available published evidence, assess the quality of this evidence, bring it together and publish evidence based recommendations. These are usually really useful documents however in the context of Bcc in CF the “recommendation” of the two systematic reviews is, “no conclusions can be drawn about the optimal antibiotic regimens for people with CF with chronic Bcc infection”… Doh! How is that helpful!!?
What studies there are have failed to show a link between laboratory sensitivity data and clinical outcome; even minimum inhibitory concentration data is not that reliable. One possible reason for this is that Bcc probably rarely causes infection on its own; it is usually part of a mixed infection. This means that antibiotics technically testing resistant might actually make the patient “better” by treating one of the other bacteria mixed with the Bcc; alternatively antibiotics testing sensitive may fail to treat another bacteria present and therefore the patient doesn’t improve even though the Bcc was actually treated... frustrating huh!?
Yet another problem with sensitivity testing Bcc is that different methods give discrepant results. Disk diffusion, Etest MIC and broth microdilution MIC all give different answers… so which one do you believe? We in the UK tend to assume broth microdilution is the best method, but we don’t really have any good evidence for this; it’s probably just the best out of a bad bunch.
The main antibiotics used to empirically treat Bcc in CF are based upon laboratory screening of thousands of isolates sent to reference laboratories to look at the relative sensitivities of the bacteria. At present the most commonly sensitive antibiotics are:
- Tigecycline (although clinical experience is limited)
Additional antibiotics that are sometimes sensitive include:
Remember, antibiotics such as Colistin and Tobramycin which are often used to treat exacerbations of CF are NOT ACTIVE.
Ideally all isolates of Bcc from a CF patient should be tested for antibiotic sensitivity by a broth microdilution assay to at least give a bit of an idea about what a particular patients Bcc might be sensitive to. Locally we tend to do this twice a year but it could be done more frequently if treatment fails.
At the end of the day this means that when it comes to treating Bcc, antibiotic regimens are chosen from “what might work” based upon laboratory sensitivity testing, “what the patient can tolerate” due to allergies and “what has worked in the past”… not very scientific really and doesn’t fill us with much confidence either, but at the moment it is all we have to go on. Maybe in the future there will be some clear recommendations, but until then we do what we can…
As for our patient in the MDT, we went for Co-trimoxazole PLUS Tigecycline for the B. multivorans but also gave Ciprofloxacin PLUS Tobramycin in case the Bcc was only part of the problem as we knew these had helped her in the past. A combination therapy of “what might work” and “what has worked in the past”! The patient did respond and was soon able to go home… which was a relief… as who knows what our next choice would have been!?