Basically, everything that was listed above. We're covering:
TMP-SMX
Quinolones/Fluoroqunolones
Rifamycins
Aminoglycosides
Tetracyclines
Glycycylclines
Macrolides
Lincosamides
Oxazolidinides
Streptogrammins
Mupiricin
Imidazolids
All PCNs/B-lactam drugs
And pretty much the full gauntlet as far as what we need to know: Names (I can do alright with that) of the specific drugs, MOA, resistance, spectrum of coverage, basic pharmacodynamics/kinetics, adverse reactions, clinical use, contraindications.
So it's a lot to me! Not sure where to start . . . .
Not a problem
I'll start with the fluoroquinolones since these are my favorites. As part of my PhD thesis I have been working on a novel fluoroquinolone resistance efflux pump.
Fluoroquinolones are a broad spectrum antimicrobials which function by inhibiting DNA gyrase and topoisomerase IV. Because humans do not produce DNA gyrase and topoisomerase IV human DNA remains unaffected. It may be a little off topic but all antibiotics but fluoroquinolones have also been shown to cause the formation of OH* (that's a hydroxy-radical :-( - I forgot I don't have chemdraw on this forum). It appears this hydroxy radical causes additional DNA damage to the microbe-thus making fluoroquinolones the efficient (microbe) killing machine that they are.
Also it appears that fluoroquinolones have some specificity of targets with regards to gram positive and gram negative pathogens. That is to say in a gram negative pathogen the drug inhibits DNA gyrase the majority of the time, and conversely it inhibits topoisomerase IV for the majority of the time as well.
Basically what happens is the DNA is trying to replicate, so you've got DNA gyrase or topoIV on the DNA strans witht he replication fork, and your fluoroquinolone just blocks the the gyrase against the DNA and blocks the replication fork. Shortly thereafter the cell dies.
Based on the medical students I've worked with- I've found that a lot of medical schools try to make you think that a single resistance mechanism is responsible for the headache resistance causes. That's not always true (otherwise I'd be out of a job lol).
One of the most significant mechanisms of resistance (as one would expect) is a mutation in the target enzyme. In fact there is a region of bacterial DNA which we have termed "the quinolone resistance determining region." These mutations tend to cause the enzyme to be impervious to the drug-(if you put some sunglasses on the enzyme the drug gets confused and cant' do anything).
Another major mechanism of resistance to fluoroquinolones is the NorA fluoroquinolone resistance efflux protein. NorA (which if I remember right is short for norafloxacin resistance protein A) is a multi-drug efflux pump. It is driven by the production of a proton gradient. (In fact one thing you can do if you get a strain with NorA is to give them a fluoroquinolone with a proton pump inhibitor like prilosec to through off the proton gradiant). -Note on this last trick I'm assuming that you are not giving an oral dosage form.
Another mechanism of resistance (which I personally was only aware of 2 days ago) is a protein called the qnrB protein. Its set with the SOS system. Basically the SOS system is exactly what it sounds like. The bacteria have a set of genes all in a row that they turn on whenever they think they're about to die (such as when cipro enters the cell). One of the genes that gets turned on this way is qnrB. The qnrB protein runs around the cell real quick and finds the DNA gyrase or topoisomerase IV before the cipro or other quinolone can find it, and it acts basically like a body gaurd. It prevents the cipro from binding to its target.
Ok as far as spectrum goes I love the fluoroquinolones because its an indiscriminant killer in the microbial world. It doesn't care if your gram positive or gram negative. If you're a bacteria, it'll kick your door down and start playing with your topoIV and DNA gyrase.
Generally speaking it is very common to use fluoroquinolones for Gonorrhea E. coli, UTI, and a number of other pathogens. In 1999 we used it quite a bit for community acquired S. aureus, but this had real disadvantages in that the blood fluoroquinolone concentration does not seem to stay high for a really long time. In conditions like MRSA induced sepsis-this was a real disadvantage! The bugs would be exposed just long enough to develop resistance. Then we noticed the trend that soon after some S. aureus strains developed resistance to fluoroquinolones resistance to methicillin wasn't far behind. But before long MRSA became more common- which once it gets to that point you've really only got vanco and a few other drugs that only an ID doctor can perscribe. Since then fluoroquinolones started to be benched when it came to MRSA infections. But more recently newer fluoroquinolones are being develope for the explicit purpose of targeting MRSA! These drugs keep up their blood concentration just as well as we would hope, and it seems they have some unique structural features. I originally thought these were "me too drugs" (that is a drug that a company develops with a slight difference from a drug already on the market so they can get around patents and those pesky lawyers), but apparently these additional structural features actually do stuff. They may increase the lipophilicity of the drug. This could be good on S. aureus because they tend to have a rather thick matrix surrounding the cells (I want to say its a glycosaminoglycan matrix, but I don't want to stear you wrong so I'll double check that). These structural features may also help the drugs get past biofilms (which can be a resistance mechanism in and of itself). When a thick enough film develops around the microbes it is difficult for the drugs to get in. One of my buddies has spent years trying to find a way to get around those things.
I'm not sure if this is enough info or too much info or what, so I'll post this and wait for your apply, and I'll bulk up the info or slim it down as you find appropriate for your individual class.
I will look up some more references for the other stuff. The fluoroquinolones I know off the top of my head because I am working on a dual PhD at UNC Chapel Hill on mechanisms of fluoroquinolone resistance in S. aureus (and ways to circumvent the problems they cause).
Also I'm just currious, but would you guys be interested in starting a pharmacology forum or an infectious disease forum in conjunction with the pharmacy side of SDN. Personally I think we could have a lot of fun with it.
Well its almost 2 PM and I haven't had lunch yet, so I'm gonna grab a bite to eat and see what you guys think
Cheers,
Zach
