A question about antimicrobial-resistance...

RE: A question about antimicrobial-resistance...

Rudo Nikisi — Tue, 31 May 2016 19:39:11 GMT

How narrow and simplistic and frankly nasty to label a happy family With a 3rd child the cause in such a complex issue. I assume you probably don't have a third child yourself, could that have been because you didn't want to contribute to the selection pressure?

RE: A question about antimicrobial-resistance...

Michael Woodhouse — Thu, 26 May 2016 18:01:28 GMT

[quote user="Julian Earl"]

Have we therefore agreed that shortening the duration of treatment and maximising the dose towithin and effective safe margins is the best way to minimise selection pressure? I think so looking at comments above...

[/quote]

No - it depends on so many things. A short course of treatment for deep pyoderma will be woefully inadequate, but for a mild eye or ear infection may be fine.

RE: A question about antimicrobial-resistance...

Julian Earl — Thu, 26 May 2016 15:08:30 GMT

RE: A question about antimicrobial-resistance...

grumpyoldman — Thu, 26 May 2016 14:24:54 GMT

tutankahamun or something similar had bacteria with resistance plamids in them, they have always been about ,but its the selection pressure that is definitely the problem.

My understanding was that several drugs are actually both cidal and static depending upon phase of illness innoculating dose etc. So a leaking bacterial cell wall , creates osmotic fragility ? and death ,but it may also allow the drugs that are static and stuff up ribosomal function in ? Hence the former success of pen/strep TMPS (folic acid metabolism ) etc .

RE: A question about antimicrobial-resistance...

Richard Carter — Thu, 26 May 2016 14:11:43 GMT

the problem as I understand is that the genetics of resistance are quite literally transferable in a mixed population of bacteria so what started out as an unintended bystander bacteria gets the dose of antibiotic as well as the genetics of how to avoid the next dose from the MRSA or equivalent bacteria or worse as a bystander bacteria not susceptible to the antibiotic, gives the MRSA bacteria the codes to become more resistant in future.

Like any selection pressure, duration and intensity make as difference on rate of development of resistance - the more effective the kill, the less around to breed, but more likely to have purified the resistance genetics (to that antibiotic).

If you have a regular change in the type of selection pressure (eg penicillins vs sulphonamides vs fluoroquinolones vs cephalosporins vs tetracyclines) then each induces a different resistance so by complete withdrawal of a group, resistance will dilute as the bacteria try survive the other selection pressures -and a complete different attack from left field leaves the bugs weakened and reduced in numbers (and of course the usefulness of bleach and general hygiene in infection control to keep the infective dose to the patient to a minimum). Similarly combination treatment will have different selection pressures on the same organism and the likelihood of being able to cope with both is obviously small.

What doesn't work is the using of cidal drugs such as penicillins that require bacterial multiplication with blockers such as tetracyclines that stop multiplication - penicillins and metronidazole is an old one but what can be given with sulphonamides or tetracyclines or fluoroquins?

RE: A question about antimicrobial-resistance...

Beats — Thu, 26 May 2016 13:34:19 GMT

I think concentration-dependent versus time-dependent can be misinterpreted here (unless I've got it wrong myself which is always very possible!).

Just for clarity, my understanding is that we're talking about best dosing-regimen when giving daily dosing (once daily or splitting the daily dose into multiple smaller administrations). i.e. an aminoglycoside probably works best by achieving the highest peak concentration you can (once daily dosing) as it kills bacterial cells at any stage in their life cycle while a beta-lactam probably works best by maintaining an adequate tissue concentration above that needed to kill the bugs for as much of the day as possible (twice/thrice etc daily dosing) as it kills the bugs mainly during cell division. This has nothing to do with the length of course (in terms of 5 days versus 10 days or something) administered as I understood it.

Re MIC: My understanding from vet school days was that this was an in vitro measurement of the kind where that was the concentration required to inhibit 50% of bugs - I thought that as a rough rule-of-thumb one was aiming to achieve tissue concentrations of about 2-3xMIC in a clinical situation.

Given that no-one can even agree on basic facts such as the half-life of antibacterials in most species, let alone tissue concentrations reached, I wholeheartedly agree though that is mostly guess work!

RE: A question about antimicrobial-resistance...

Iain Richards — Thu, 26 May 2016 11:43:52 GMT

Time dependent vs concentration dependent is correct as far as I understand it, but a crucial issue is that no-one knows how long to give them and "complete the course" may be erroneous. There are a lot of parallels with anthelmintic resistance, so learnign from SCOPS could be a good plan.

RE: A question about antimicrobial-resistance...

Hannah Wynne Richards — Thu, 26 May 2016 09:44:57 GMT

100% agreement with grumpyoldman. Farm gate prices for animal products need to be an absolute minimum of 5 x current levels to allow decent standards of care, and decent profits, then the problem will solve itself.

I attended the last proper BVA Congress (Liverpool 2012) One of the Leahurst lecturers was talking about antimicrobial resistance in farm animals. His lecture ended with a slide of his 3 children. He stated that his priority was safeguarding their health. I was feeling polite (glass of wine at lunch time) so didn't say it, but I felt like saying that his 3rd child, and all other 3rd or subsequent children were the cause of the problem................unnecessary numbers of people leading to a production pressure, leading to antibiotic use to control diseases which wouldn't exist on small wealthy farms.

Wynne

RE: A question about antimicrobial-resistance...

grumpyoldman — Thu, 26 May 2016 00:04:51 GMT

Panorama at it again ?. There was a fair bit of drama, unfortunate people in hospital with nasty Klebsiella infections that were resistant to everything etc.

Blaming farmers etc however bacteria have always had Plasmids ,and they have always behaved like teenagers on a Friday night . Its certainly something to think about ,and more culture and sensitivity prior to targeted therapy is the way forward when there is time and money . But that did appear to be the crux of the problem,as always, money ,too many people wanting cheap food at all cost.

RE: A question about antimicrobial-resistance...

Evelyn Barbour-Hill — Wed, 25 May 2016 23:32:12 GMT

[quote user="Julian Earl"]

Evelyn: By partially-resistant I meant bacteria thatare resistant unless the concentration is high enough, or Where a whole species is not sensitive, and so on. Have I made this concept up?

[/quote]

Oh, I see.

RE: A question about antimicrobial-resistance...

Michael Woodhouse — Wed, 25 May 2016 22:47:34 GMT

[quote user="Scarlett Creasey"]Please let me know if I am incorrect as I am still learning (obviously!)[/quote]

So far the best answer goes to the student, IMO!

In vet medicine we seem to have simplified the time and concentration dependant concept - whereas the medics seem to acknowledge some antibiotics have aspects of both. Your penicillin/cephalosporins are the traditional time dependant antibiotics. As long as we are above the MIC then it it the time that matters - so sufficient dose for longer achieves a 'better' kill - the area under the curve.

The traditional concentration dependant antibiotics would be the fluoroquinolones and aminoglycosides. In these cases duration of treatment is less important and a single (massive) dose makes sense for efficacy and responsible use.

The medics then go on and classify mainly the macrolides and tetracyclines as a bit of both.

http://www.medscape.com/viewarticle/563444

The closer we dose to the MIC the less time the drug spends above MIC. Subtheraputic doses promote resistance. Higher doses may be more likely to cause side effects and will be more costly to the owner. We don't know the bacteria involved or its MIC - often we are treating on a best guess or whilst awaiting culture and sensitivity. Length of course would also be related to a huge number of factors - blood supply, ion trapping, lipid solubility, ongoing re-infection, nidus of infection, type of infection, immune status of the patient etc.

The way I explain partial resistance to farmers is that we each carry two copies of each gene. This is the same in bacteria. If the bacteria carries two susceptible genes it is easily killed. If it contains two resistant genes then it is very hard (or impossible) to kill. If it has one of each it sits in the middle - under-dosing, short courses etc kill off the very susceptible bacteria and leave mainly resistant and partially resistant bacteria behind. A longer course (at an appropriate rate) is more likely to remove the partially resistant strains (as antibiotic levels increase above MIC). A higher dose is more likely to kill off partially resistant strains.

My view is we need a dose as high as is safe for as short as possible, but as long as is necessary. We also need to stop using antibiotics for prophylaxis.

RE: A question about antimicrobial-resistance...

Julian Earl — Wed, 25 May 2016 22:31:39 GMT

Evelyn: By partially-resistant I meant bacteria thatare resistant unless the concentration is high enough, or Where a whole species is not sensitive, and so on. Have I made this concept up?

RE: A question about antimicrobial-resistance...

Evelyn Barbour-Hill — Wed, 25 May 2016 22:23:04 GMT

[quote user="Scarlett Creasey"]From what I understand, antibiotics can be either concentration-dependent or time-dependent, which I think is linked to whether they are bacteriostatic or cidal.[/quote]

No, I don't think it's linked to whether they are 'static or 'cidal.

RE: A question about antimicrobial-resistance...

Evelyn Barbour-Hill — Wed, 25 May 2016 22:20:47 GMT

When the antibiotic resistance fuss really began... about 1967?....we were told that doses should be high and courses should be long. Even then I couldn't see the logic.

Minimum effective doses and courses as short as possible will surely exert the least selection pressure?

I also have some trouble with the idea of individual bacteria being "partially" resistant.

RE: A question about antimicrobial-resistance...

Scarlett Creasey — Wed, 25 May 2016 21:42:34 GMT

From what I understand, antibiotics can be either concentration-dependent or time-dependent, which I think is linked to whether they are bacteriostatic or cidal. Some concentration-dependent antibiotics would be suitable for higher dose suitable and shortest course possible, and I was under the impression that this was already done for these drugs?

For time-dependent antibiotics the amount of time the drug is above the minimum inhibitory concentration is the limiting factor, so no matter if you increase the dose, the efficacy will not change.

Please let me know if I am incorrect as I am still learning (obviously!)

Scarlett