Great concern – requesting an answer

Question

Dear expert team,

A friend of mine has CF. She now has the following germs in her sputum: high counts of Pseudomonas fluorescens, Burkh. gladioli, Enterobacter, Candida albicans, and masses of Haemophilus parainfluenzae. The Burkh. gladioli had been detected often before. The Pseudomonas is new. She has had repeated iv antibiotics therapies, which she never tolerated well. She often did not tolerate tablets well, either (diarrhea). Recently she has been doing inhalations with TobiPodhaler®.

Now my friend is supposed to get an i.v. therapy with the following four drugs: Genta® (gentamycin), Tobi® (tobramycin), meropenem, and either Zienam® (imipenem/cilastatin) or ertapenem. The rest of the therapy looks like this: Mucoclear® (hypertonic saline) 4x3 daily, Atrovent® (ipratropium bromide) with Sultanol and 0,9% NaCl three times daily, Pulmozyme® (DNAse) 2x1 and Toby® (tobramycin) dry inhalation 2x daily, plus physiotherapy 2x daily.

We are concerned about this strong i.v. therapy. Would it make sense to get a second opinion (CF clinic)? Or is such a strong therapy the only way to help in this case? Do you have any experience with this combination of drugs?

And another question: Which significance does the Burkholderia gladioli have? Is it dangerous, does one have to be isolated with it? Can one go into rehabilitation treatment with this germ?

Many thanks for your answer, and please excuse the number of questions.

Answer

Dear questioner,

Many thanks for this question, which is indeed not so easy to answer. Your friend seems to be infected with various germs. As far as I understand it, with Burkholderia gladioli for some time now, newly with Pseudomonas fluorescens as well, and probably also with further germs less relevant for her clinical condition (Candida, Haemophilius, and probably also Enterobacter). Concerning the Burkholderia gladioli, the data situation about its influence on the progression of CF is a bit insecure (Kennedy et al., JCF 6 (2007) 267–273). There is data, however, that shows that Burkh. gladioli can lead to severe complications especially after lung transplantation (Brizendine et al, Transpl Infect Dis. 2012 Aug;14(4):E13-8).
Concerning Pseudomonas fluorescens the finding has to be controlled once more, as it can come to misclassifications of a "real" Pseudomonas aeruginosa as a Pseudomonas fluorescens due to automate analysis. Indeed the Pseudomonas fluorescens belongs to the same group as the feared Pseudomonas aeruginosa, however there isn't any data proving chronic colonization of the CF lung nor worsening of the lung function due to this germ. A probable therapy depends on the clinical situation of the patient. However the mentioned therapy (inhalation of tobramycin) sounds more like treating Pseudomonas aeruginosa and if this germ is really present, at least concerning children/adolsescents, it is relatively clear that eradication should be attempted (Davidson et al, Curr Opin Pulm Med. 2012 Nov;18(6):615-21).

However, I cannot make a statement here about whether an eradication attempt would be promising or not without knowing your friend’s exact history, particularly the severity of her CF-related problems (general health condition, weight, lung function, nature of bronchiectases, etc.) Above all, the question is also what the goal of the i.v. therapy is: Is your friend’s health status currently severely limited and an i.v. therapy thus indicated imperatively, or does one just want to eradicate the Pseudomonas and the Burkholderia? Regardless of the goal of the i.v. therapy, the kind of antibiotic therapy chosen is targeted at the germ one would like to treat. The choice of antibiotics is based on experiences from earlier i.v. therapies (which therapy brought clinical improvement, are there any allergies against certain antibiotics?) and also on potential resistances against the germs to be treated. Since I do not know which germ is supposed to be treated (I am guessing probably Pseudomonas and Burkholderia), which resistances your friend may have, and whether she has any allergies, I cannot comment on the antibiotics chosen here. However, it is indeed the case that, depending on resistances and especially if one wants to treat against Burkholderia, one always has to do an i.v. therapy with several antibiotics in order to treat the (usually rather resistant) germ successfully. Furthermore, Pseudomonas is practically always treated with two antibiotics from two different classes (usually one aminoglycoside such as tobramycin, gentamicin or Amikin®/amikacin sulphate, and a so-called beta-lactam such as meropenem).

I am a bit confused by the combination of Genta® and Tobi®. I do not think both are supposed to be given intravenously (increased renal toxicity), but that Tobi® will be inhaled. It is unclear how sensible it is to continue inhalation therapy with Tobi® while at the same time giving a second aminoglycoside, and different CF centres handle this differently. In our centre, we usually pause inhalative antibiotics therapy with Tobi® during i.v. therapy with an aminoglycoside. I also do not know of a combination of meropenem and imipenem or ertapenem (all three are antibiotics of the so-called carbapenem group) as a standard therapy, and we never use it.

Since this seems to be a very complex case and I am not sure about the combination of the different antibiotics, it would certainly make sense to discuss this therapy again very thoroughly with the treating doctors and to perhaps even get a second opinion from an experienced CF centre. Based on the international guidelines, it would be reasonable if all CF patients were treated in designated CF centres (Colombo, Littelwood, JCF, Volume 10 Suppl 2 (2011) S7–S15.).

Concerning your final question on whether your friend may go into rehabilitation treatment or not, the answer again is not so easy. It is unclear in how far transmission from patient to patient is possible. A case description from the 1990s about transmissions in a CF population showed on hindsight that the germ in question was not B. gladioli but B. cenocepacia (Clode et al, Am J Respir Crit Care Med. 1999 Jul;160(1):374-5). However, there are current case reports of so-called nosocomial infections (acquired in the hospital) in a newborn ward (Dursun et al, Eur J Pediatr. 2012 Oct;171(10):1503-9. Epub 2012 May 31). Since the data situation concerning transmission is unclear (probably mostly directly from the environment) and, as mentioned, the infection with Burkholderia gladioli can lead to a severe progression of CF and pose a problem especially also after lung transplantation, all patients in our CF clinic are immediately isolated on principle (like patients with a different CF-relevant infection of the Burkholderia group). Correspondingly, our patients are also isolated strictly at the rehabilitation clinic.

I do hope I could help clarify your questions and wish you and especially your friend all the best.

Dr. med. Markus Hofer
Adult CF clinic
Zurich University Hospital

08.01.2013