What is heteroresistance?

Recent cases of coagulase negative staphylococci, that were very difficult to eradicate, have led to an assessment of whether the phenomenon of heteroresistance may play a part. To be honest, for me this is entirely new; I was not aware of this phenomenon until very recently.

The idea is that colonies of the organisms involved in an infection have subpopulations that have much less susceptibility to antibiotics, in this instance to vancomycin. In the lab the germ will test sensitive to the antibiotic, but in reality it will be very difficult to eradicate the bug. In fact, what is seen is that about 1 in 100,000 to one in 1 million of the germs are more resistant to the antibiotic, if you sub-culture the susceptible strain you will again find that the germ is sensitive, but there is again a subgroup of about 1 in 100,000 to 1 in 1 million organisms that are much more resistant. Now, I hate not understanding things (except theoretical physics that I have accepted that I will never understand (but according to Richard Feynman, that is just fine because no-one does*)) so if anyone can explain the molecular basis of this, please let me know what is happening.

Anyway… these bugs seem to be sensitive on standard lab testing, but when specific ‘other tests’ are performed, there is again a subgroup that are resistant. It may be the first stage in evolution of antibiotic resistance.

A recent publication from France reports a very worrying trend of increased prevalence of heteroresistant coagulase negative staph (often referred to as CoNS). (Rasigade JP, Raulin O, Picaud JC, Tellini C, Bes M, Grando J, Ben Said M, Claris O, Etienne J, Tigaud S et al: Methicillin-resistant staphylococcus capitis with reduced vancomycin susceptibility causes late-onset sepsis in intensive care neonates. PLoS One 2012, 7(2):e31548.
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0031548#pone.0031548-Ng1)  The two other publications from NICUs that I have seen, also report this as a feature of S capitis, but in other patient populations, by which I mean adults, the phenomenon can affect not just capitis, but other CoNS species, such as S epidermidis and S hominis. And indeed the phenomenon was first noted with S aureus.

Clinically what is evident is persistent bacteremia despite good vancomycin serum concentrations, and often despite removal of central lines (Van Der Zwet WC, Debets-Ossenkopp YJ, Reinders E, Kapi M, Savelkoul PHM, Van Elburg RM, Hiramatsu K, Vandenbroucke-Grauls CMJE: Nosocomial spread of a staphylococcus capitis strain with heteroresistance to vancomycin in a neonatal intensive care unit. Journal of Clinical Microbiology 2002, 40(7):2520-2525.
http://jcm.asm.org/content/40/7/2520.abstract).

What to do about this is not yet totally clear, the first thing to do is to recognize it; standard sensitivity techniques do not work, specialized approaches are required. Once identified, do we just push up the vancomycin levels or add (or change to) other antibiotics, agents such as linezolid, daptomycin and tigecycline may be indicated. None of which I know much about, but linezolid use in the newborn has been reported a few times; there is some data about kinetics and toxicity, and it has been successful in clearing persistently positive cultures in reported cases, with low toxicity. There are reported cases of neutropenia in older patients, this has not been the case in newborns and young children and there are now reports of more than a couple of hundred young children and newborns treated with Linezolid in whom there was surveillance for neutropenia.

Linezolid is sometimes referred to as being bacteriostatic, but in reality the distinction between ‘static and ‘cidal antibiotics is of little clinical significance, if any. It is generally accepted that bactericidal activity may be important for treating meningitis and endocarditis, for other infections there is no proven advantage. Indeed the distinction between bactericidal and bacteriostatic drugs is quite unclear, many bacteriostatic drugs do kill bacteria, and bactericidal drugs often do not kill 100% of the germs within 24 hours. (Pankey GA, Sabath LD: Clinical relevance of bacteriostatic versus bactericidal mechanisms of action in the treatment of gram-positive bacterial infections. Clinical Infectious Diseases 2004, 38(6):864-870.
http://cid.oxfordjournals.org/content/38/6/864.abstract).

The paper that I referred to above, from Van Der Zwet, reports clonal spread of a heteroresistant CoNS in their NICU over a 4 year period until it was finally recognized. The prolonged positive cultures that are seen in such cases are a real worry, infants who have prolonged inflammation as a result of delay in eradication of CoNS have worse long term developmental outcomes, possibly as a result of the effects of the inflammatory mediators over a long period on the brain.

The important factors for our babies appear to be:

1. do whatever you can to reduce the prevalence of nosocomial sepsis.

2. that includes removing lines and reducing the duration of broad spectrum coverage

3. Make everyone wash their hands (this should be considered MANDATORY, anyone not washing their hands before touching a baby should be fired)

4. do whatever you can to reduce the prevalence of nososcomial… (OK I know I can be annoying at times)

5. when you have CoNS, consider testing for heteroresistance

6. eliminate the more resistant organisms with something (probably with one of the new antibiotics, but with the certain understanding that one day those fancy, (I hesitate to say clever because there is no intelligence required, it is just evolution) staph will become resistant to the new one as well).

7. Make everyone wash their hands, CoNS appear in the blood stream of our tiny fragile babies because they were on the skin of a health care worker, and the health care worker touched something, a tube, a catheter or the abdominal skin of a baby, without washing their hands well enough.

8. Make everyone wash their hands.

Isn’t it weird that in the same post I can talk about quantum physics and about how much we need to wash our hands?

* ‘If you think you understand quantum theory, you don’t understand quantum theory’. A frequently re-quoted quote, but it is not certain that he ever said it…

About keithbarrington

I am a neonatologist and clinical researcher at Sainte Justine University Health Center in Montréal
This entry was posted in Neonatal Research and tagged , . Bookmark the permalink.

One Response to What is heteroresistance?

  1. katharinastaub says:

    Oh, this is after my heart. WASH THOSE HANDS!! AS a parent and person very involved in this neonatal world, I see most nurses with rings and other things hanging on their arms, physicians with phones etc… these are the parents’ babies.

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