I know we've already talked a lot about resistance and in this section we're going to talk about those specific mechanisms of resistance that bacteria have resistance is a real issue and I grabbed this picture just so that we can see how resistant organisms have become over the years so the first picture on the left this is from 1991 and all of those little white dots that's actually antibiotic and when that antibiotic is applied to a lwn of growth when it kills the bacteria we see a clearing we call that clearing a zone of inhibition so if you look at this clearing and I'm just going to circle a clearing around one of those discs you can see that the bacteria has been killed so you can see in the first plate in 1991 there are several antibiotics that are doing a good job of actually killing the bacteria you can see a couple on the plate where they are resistant so I'm just kind of pointing those out so you see no zone of inhibition and you can see growth all over that disc so that means that that organism is resistant but most of those antibiotics in 1991 we doing a pretty good job of killing the bacteria if you take a look at the picture from 2021 taking those same antibiotics you can see that there's only a couple that actually worked where that bacteria was susceptible so we know that resistance has increased over the years and this is a big issue and one of the things that we'll talk about is how is it that we can prevent resistance so resistance means that an organism that at one time was susceptible that could be killed by that antibiotic now that antibiotic no longer affects it so how does resistance actually happen well through the previous chapters we talked about increasing genetic diversity in bacterial populations so we talked about transformation and we talked about conjugation so we know that genetic changes can occur by those bacteria acquiring those genes so they can acquire resistance genes so this allows resistance to antibiotics to spread through populations rather quickly one of the ways that antibiotics can kill bacteria is to interfere with the making of their cell wall that peptidoglycan sometimes bacteria can actually go into an L form an L form is when when they stop making a cell wall for several Generations so the antibiotics that are targeting that cell wall are not going to work because those bacteria are able to survive without that cell wall we also know that some bacteria are very small they can hide in cells and they can also hide in tissues like tuberculosis in the lung if we look at some other mechanisms of resistance one of the ways that bacteria can develop resist through alteration of targets so if let's say that we design an antibiotic to Target a certain protein on that bacteria if a mutation in the DNA happens to change that protein now that antibiotic is no longer going to affect that protein it's no longer going to be able to bind to it so if mutations happen now that antibiotic is going to be useless now we know that bacteria can reproduce very quickly so mutations can happen very quickly we also know that some antibiotics will work by targeting the bacterial membrane so if we develop an antibiotic that hits that membrane if mutations happen where now those membrane proteins are not going to bind to those antibiotics and that antibiotic can't get through that membrane now that bacteria is going to be resistant to that antibiotic some bacteria can actually develop enzymes that will break down the antibiotic so we talked about those beta lactum Rings interfering with how the bacteria makes that peptidoglycan some bacteria can make betal laumas this is an enzyme that breaks down the betal laum ring so when they see that betal laum ring the enzyme gets to work and destroys it we also know that bacteria can alter enzymes so we talked about some of those Inhibitors so those antimetabolites so if we develop an antibiotic to affect an enzyme but even when that antibiotic IC binds to it as an inhibitor that enzyme is still able to work and that bacteria is able to continue with its metabolism now that bacteria can still make its energy source so it's not going to be affected if we develop an enzyme to Target certain parts of a metabolic pathway and that bacteria now has the ability to bypass that then it's going to be able to live so these bacteria can be very sneaky in evading these antibiotics so for me I have to draw things out so I think it's a little easier to kind of see from a picture so I've tried to draw each of these out so the first one is the alteration of targets so if we design a drug to bind to a protein to bind to a receptor if im mutation happens where now that antibiotic can no longer bind to it now that antibiotic is not going to affect it so you can see from my first picture on the left that antibiotic com bind to that receptor but then in the second picture because of IM mutation that receptor is changed now that antibiotic no longer binds to it the second one the middle picture is alteration of membrane permeability so if we design a drug and it can easily penetrate the me brain um it's going to harm that bacteria but if that bacteria develops a way to stop that antibiotic from penetrating through the membrane now that antibiotic is not going to be able to get through it's not going to be able to cause harm the beta lactamase so you will see my beta lactamase on the bottom picture kind of looks like a pacman kind of looking figure and then we have that beta laum ring from those antibiotics like penis cin that betal lactamase can gobble up that betal laum ring destroy it so now it no longer impedes the development of the peptidoglycan synthesis alteration of enzymes so there's my little Pacman enzyme at the Top If we design a drug to inhibit it slow down that enzyme so that bacteria can't complete its metabolism if it is able to still operate in the presence of that inhibitor that enzyme still functions it's not denatured then that antibiotic really isn't going to do anything to that bacteria's metabolism and then finally alteration of metabolic pathway so if you see on the left a goes to B goes to C goes to D so if this is the normal pathway of metabolism if let's say that we design a drug to Target B so the intermediate B in this pathway in order for the bacteria to get the product D that it needs for its metabolism if we target b and we take B out now it's not going to continue with its metabolism however if that bacteria now can find a way around having to go to intermediate B and it can bypass it and go from a to c now it no longer needs be so that antibiotic isn't going to do anything to it so a little bit more on Resistance if you go to the doctor and you are prescribed an antibiotic this is usually what we call a firstline drug so you go to the doctor for maybe a cellulitis or strep throat they're going to prescribe an antibiotic hopefully that first line drug the first antibiotic that worked actually does its job if let's say that you start feeling a little better and then after a couple of days um you're starting to feel bad again now you're going to go back to the doctor and they're going to prescribe a second line drug so that bacteria has become resistant it's found that work around it's developed one of those mechanisms so if you go back back and you tell your clinician you know this I'm antibiotic is not working I'm still not feeling great they're not going to prescribe a drug that is going to work by a similar mechanism because we could have cross resistance so if we prescribed another antibiotic that's going to have a beta leum ring but that bacteria has developed that enzyme that betal lactamase it's not really going going to be helpful to add that antibiotic because it's not going to work in fact it could actually do more harm because it's going to continue to get rid of the the good microflora that you have so you certainly don't want to prescribe a second line drug that works by the same mechanism because that bacteria is already proven that it's got to work away around that antibiotic killing it so what can we actually do to limit drug resistance so first of all when we're prescribed antibiotics we should take that dose that should be high enough with that long course to actually kill all of the pathogens so we want to make sure when we're prescribing as clinicians that we're prescribing a high enough dose and that we prescribe it for a long enough course to actually kill all of the pathogens and any of the mutants the other thing that clinicians sometimes do is that they will actually add two antibiotics together so they end up having a synergistic or an additive effect so for example you might prescribe penicillin and streptomycin so penicillin can inhibit the cell walls because it has that beta lactum ring and that's going to allow strep amiin in to do its job on the proteins as an aminoglycoside another um drug that you've probably heard of is Augmentin and Augmentin has amoxicilin and it also has cavalon acid so if that bacteria has a beta lactamase enzyme to break down that beta lactum ring the cavalon acid actually ties up that enzyme and keeps it from inactivating Amoxicillin so that it can actually get in and do its job um if you've ever had Augmentin or if you've ever given Augmentin to Children um it doesn't taste as good as a moxacin but um I can tell you from experience with my kids it actually does a better job at least it did for the infections that that we had in our house the other thing is that we want to restrict antibiotics for essential use so if somebody has a flu virus you don't want to prescribe an antibiotic because it's going to do more harm than good long gone are the days that you could call up the doctor and say yeah I think I've got a strep throat can you prescribe an antibiotic um they want to see you they want to make sure that that antibiotic is necessary so we don't want to overprescribe antibiotics of course when they're necessary we want to use them so I mentioned making sure that we are using a high enough dose and taking our full medication so every time that I'm an an antibiotic and I often forget to take a dose my mind automatically goes to this picture so this kind of takes us through uh a typical regimen of antibiotics and if we had an infection so if you take a look at the top chart on day zero this is based basically a bell curve of the bacteria in our infection so let's say that we have a strep throat infection so here's the bell curve of the bacteria that's causing this infection so on the one side we've got our highly sensitive organisms so as soon as we start taking that antibiotic they're going to be knocked back then on the other side we've got highly resistant organisms it's going to take quite a bit to actually make a dent in that population the majority of them are probably going to fall somewhere in between so they're going to be intermediate so we go to the doctor we explain that we are not feeling well our clinician prescribes an antibiotic for us so as you know in the beginning we are good patients because we want to feel better so for the first few days we're doing a good job we're being the best patient and we're taking our antibiotics so by about day three you'll notice that we've started to make a dent in those highly sensitive organisms and a pretty good dent in the intermediate organisms you notice that we haven't really hit those highly resistant organisms it's going to take a little longer to actually knock those back but we're going to be good patients so we're going to continue to take our antibiotic and if you take a look at day six we've pretty much knocked back all of those highly sensitive organisms we've made a really good dent in the intermediate organisms and now we're finally starting to make a dent in our highly resistant organisms it's probably at this point that we're probably feeling a little better so we're probably getting more sleep we're also eating better so our immune system is also helping to to knock this bacteria down so we're very good patients we take our antibiotic for the full 10day course and we've pretty much knocked back all of those pathogens and now our immune system can kind of keep everything at Bay and we're feeling better so this is if we're really good patients now you know what happens life gets in the way right and sometimes we get forgetful especially if we are starting to feel better we think well you know it's okay if I miss a dose or to so let's go back up to day six so day six is about we're we're really making a dent in this population so we're starting to feel better we're probably going about our daily activities and so this is when we get forgetful we're not taking our antibiotic and we're like yeah you know what I missed a few dos I'm you know I think I'm feeling better I think I'm good so if we stop taking our medicine for about 4 days look at what happens at day 10 you notice that the population that has really taken off is our highly resistant organisms so we have given them the chance to take off and so now they are really abundant and so now if we start taking our antibiotic now it's not going to work as well because of those highly resistant organisms so now we're going to have to go back to the clinician and have them prescribe us um a a second line drug the other problem with this is that as we're going about our business we're feeling better we're going back to work we're going back to school now we're also spreading this resistant bacteria to everybody we know and next thing you know our family members are sick or our friends our co-workers are sick as well so I always think of this picture every time I forget a dose I don't want this to happen um and so if I forget a dose I try to get right back on the the good patient train and continue to take our my antibiotics the other thing that we should also not do is to take somebody else's antibiotic uh you know we've all done it um but that puts us all at risk risk so the person that should be taking it they're not getting their full dose and we're obviously not going to get the full dose as well and that's probably going to set us all up for a second line drug so the next time that hopefully you're not on an antibiotic anytime soon but if you are um perhaps you will also be thinking of this picture as well um since this is something that is so common and um something that we definitely need to think about as far as resistance spend a little time with this graph if it helps to kind of draw out the graph and explain what's happening um I think it can really help to kind of drive home that point