Re: induced, non-mutational efflux-based resistance in bacteria?

[Guest guest]

It was nice to read practical experience- firing away with the

combo and not giving a break worked well..I sort of tend to think the

regrown ones during a break are the ones that nail you most in the

ilness process IMO..

tony

>

> I've been aware that P. aeruginosa and Mtb can up-reg their efflux

> pumps by at least ~10x when assaulted by abx. I say at least because

> these may have been short term experiments. I'm not sure if the 10x

> up-reg was enough to significantly change resistance.

>

> A new PLoS One paper (free) says:

>

> " We have previously demonstrated that it is possible to induce

> high-level resistance to tetracycline (TET) in susceptible

Escherichia

> coli K-12 by a gradual, step-wise increase in the exposure to the

> antibiotic [5]. The induction process takes about 110 days and this

> resistance can be reversed by either transfer to drug free medium or

> by the use of Phe-Arg-napthylamide (PA & #946;N), an inhibitor of the

AcrAB

> efflux pump system [3]–[5]. "

>

> Someone might want to study ref 5 and see if their work is any good.

> I'm not really interested enough to read it: right now my

> thoughts/instincts/prejudices are telling me to fire away with my

> heavy abx combos without pause, rather than pulsing. I'm thinking

that

> with slow-growing bacteria the only way to kill them may be to wear

> them down relentlessly over a long period of time. Yet it's also

> possible that pulsing could have some virtues. Too bad it's all

> sooooooo speculative in the end. For me, my biggest improvements

> (during summer 2005) came during generous use of doxy and tini

without

> any breaks that I can recall... certainly none more than a few days

> long, if any.

>

> Ah jeez, I broke down and took a quick look at ref 5. It's free:

>

> http://www.pubmedcentral.nih.gov/articlerender.fcgi?

tool=pubmed & pubmedid=16048990

>

> Looks like the tetracycline resistance they obtained was 6-fold (in

> terms of the MIC). Resistance to other abx was simultaneously

obtained

> (presumably because one or more of the efflux pumps induced was a

> nonspecific one): mostly around 4-fold changes in MIC. I would say

> these changes are probably kind of borderline in practical

importance.

>

[Guest guest]

>

> It was nice to read practical experience- firing away with the

> combo and not giving a break worked well..I sort of tend to think the

> regrown ones during a break are the ones that nail you most in the

> ilness process IMO..

> tony

>

Yeah... let's assume you feel better pretty rapidly after you kill

bugs (something I am actually not too certain of). If you've been on

drugs X, Y, and Z for 6 months every day, and you're improving the

whole time, then you're killing them the whole time, progressively.

Why? Why did some of them die only after 5 months of heavy

bombardment? It's hard to see why that would happen, other than that

the *cumulative* stress, over months, eventually makes it impossible

for them to continue their metabolism, or makes them " sick " enough

that they can no longer effectively dodge and block what your immune

cells are trying to do. What other explanation is there, besides

cumulative stress (bearing in mind that it could be something

unexpected that we just haven't thought of)? (Also bear in mind that I

was making an unverified assumption in sentence one of this paragraph.)

Well, one other possibility has to do with biofilms. In at least some

environments (and my guess would be that the human body is one of

them), cells in the center of the film are nutrient-deprived and

hypometabolic. Cidal drugs have a tough time killing these, but can

kill the cells at the film's periphery. Once killed, those cells stop

exuding film. Thus, if the film material experiences significant

attrition over time (I'm not sure it does), the biofilm structure

should dissolve from the outside progressively inward. Cells at the

core's film would then be closer to the surface, receive more

nutriment, and start metabolizing more, rendering them more suceptible

to cidal abx.

[Guest guest]

Sequestration by other (larger) organisms which are not sensitive to the given abx, but which somehow die at some stage, aided or unaided, maybe

Nelly

[infections] Re: induced, non-mutational efflux-based resistance in bacteria?

>> It was nice to read practical experience- firing away with the > combo and not giving a break worked well..I sort of tend to think the > regrown ones during a break are the ones that nail you most in the > ilness process IMO..> tony> Yeah... let's assume you feel better pretty rapidly after you killbugs (something I am actually not too certain of). If you've been ondrugs X, Y, and Z for 6 months every day, and you're improving thewhole time, then you're killing them the whole time, progressively.Why? Why did some of them die only after 5 months of heavybombardment? It's hard to see why that would happen, other than thatthe *cumulative* stress, over months, eventually makes it impossiblefor them to continue their metabolism, or makes them "sick" enoughthat they can no longer effectively dodge and block what your immunecells are trying to do. What other explanation is there, besidescumulative stress (bearing in mind that it could be somethingunexpected that we just haven't thought of)? (Also bear in mind that Iwas making an unverified assumption in sentence one of this paragraph.)Well, one other possibility has to do with biofilms. In at least someenvironments (and my guess would be that the human body is one ofthem), cells in the center of the film are nutrient-deprived andhypometabolic. Cidal drugs have a tough time killing these, but cankill the cells at the film's periphery. Once killed, those cells stopexuding film. Thus, if the film material experiences significantattrition over time (I'm not sure it does), the biofilm structureshould dissolve from the outside progressively inward. Cells at thecore's film would then be closer to the surface, receive morenutriment, and start metabolizing more, rendering them more suceptibleto cidal abx.

[Guest guest]

You can buy billions of beneficial bacteria in a powdered form YEAH.

Well IMO, or my understanding of what keeps occuring- is that every

cycle of suffering can deposit bacteria into the plague formations

which needs to be broken down to get rid of all the bugs..So the bugs

keep being released from this ongoing source of supply rather than

some imaginary brain power or playing hide and seek by the bugs..

> >

> > It was nice to read practical experience- firing away with

the

> > combo and not giving a break worked well..I sort of tend to think

the

> > regrown ones during a break are the ones that nail you most in

the

> > ilness process IMO..

> > tony

> >

>

> Yeah... let's assume you feel better pretty rapidly after you kill

> bugs (something I am actually not too certain of). If you've been on

> drugs X, Y, and Z for 6 months every day, and you're improving the

> whole time, then you're killing them the whole time, progressively.

> Why? Why did some of them die only after 5 months of heavy

> bombardment? It's hard to see why that would happen, other than that

> the *cumulative* stress, over months, eventually makes it impossible

> for them to continue their metabolism, or makes them " sick " enough

> that they can no longer effectively dodge and block what your immune

> cells are trying to do. What other explanation is there, besides

> cumulative stress (bearing in mind that it could be something

> unexpected that we just haven't thought of)? (Also bear in mind

that I

> was making an unverified assumption in sentence one of this

paragraph.)

>

> Well, one other possibility has to do with biofilms. In at least

some

> environments (and my guess would be that the human body is one of

> them), cells in the center of the film are nutrient-deprived and

> hypometabolic. Cidal drugs have a tough time killing these, but can

> kill the cells at the film's periphery. Once killed, those cells

stop

> exuding film. Thus, if the film material experiences significant

> attrition over time (I'm not sure it does), the biofilm structure

> should dissolve from the outside progressively inward. Cells at the

> core's film would then be closer to the surface, receive more

> nutriment, and start metabolizing more, rendering them more

suceptible

> to cidal abx.

>