welcome back today's lecture will be on antimicrobial drugs but before we get started with the lecture let's go ahead and turn our attention to today's question of the day which is what is the order for the stages or the different stages of a phage infection do you remember have you reviewed them so think about it pause and let's continue so the first stage remember is going to be here comes my fate it's going to through random collision boom by into a bacterial cell so that is referred to as attachment attachment will be followed by entry entry of the viral DNA this will be followed by think about it synthesis so all the various little parts that make that bacteriophage are going to be synthesized or made and this will be followed by the Assembly of those little bacteria fudge after assembly how does the bacteria fadh2 get out to infect other bacterial cells through release and in this case release of the bacteriophage would be through lysis of the cell let's go ahead and continue with our lecture let's go over a little bit of the history of antimicrobial drugs beginning with quinine a really you know that's one of the earlier drugs that antimicrobial drugs add we can talk about and um this was actually extracted from the sink ona tree bark and this was used this bark has we know medicinal properties that had been used by the even the native South Americans okay and this bar contains anti malaria an anti malarial compound called quinine so this has been used for the treatment of malaria then we have Ehrlich his name was Paul Ehrlich he is credited for developing the first what we called magic bullet and this was a drug called salvarsan that selectively would find and destroy pathogens but not harm the host so that's very interesting so this is the basis for chemotherapy all anti microbials are considered chemo therapeutic agents but not all our chemo or anti microbial okay so drug this drug salvarsan was you know Ehrlich introduced it in 1908 and this was at that time referred to salvarsan 6:06 and the reason that it was called salvarsan 6:06 was because of the 606 attempts that he made to try to get this to work all right so Savarin was the first synthetic antimicrobial drug no synthetic hmm okay so we'll talk about what that means so Paul Ehrlich was a German scientist and he used this drug actually serve or serve salvarsan to treat syphilis now this brought a lot of rage in the community because they you know many people believe that these individuals that were infected with what syphilis were in morale so why should you try to find a cure for them but you know what he didn't believe that it was immoral and he used it to cure syphilis the next individual that's important in the history of antimicrobial drugs is dog Mac and he was a German chemist ger hard dog Mac and he's the one that's credited for the first sulfa drug called pronto so now this is an industrial dye that actually had antibacterial action this dog Mac actually ended up being awarded the Nobel Prize in 1939 and you see a picture of him down there but the Nazi ordered him to decline the price so that's pretty unfortunate so now let's talk about the discovery of antibiotics or modern antibiotics and we go back to Alexander Fleming who in 1929 he wrote a paper on his accidental discovery of penicillin so yes this was considered a lucky accident and so there you see Alexander Fleming and in the bottom you see a representation of what it is that he discovered so what he was doing is he had a culture of Staphylococcus aureus that he was growing in this plate here this looks like it's a blood agar plate and what he noticed when he took his plate out of the incubator perhaps is that the Staphylococcus aureus had been its growth had been inhibited by a fungus whoa that was the first time that anybody had seen that so this is referred to as anti bios's anti bios's refers to the inhibitory reaction between colonies on a solid media so basically one organism inhibits the growth of another so this is actually as far as his paper documented that Staphylococcus aureus was inhibited by a mold contamination and this mold was Penicillium penicillium notatum to be exact and we know now that it's active compound is penicillin so that was it although he's the one that gets all the credit right for discovering penicillin well yes he is the one that discovered this mold Penicillium through a lucky accident however it was Chaney and Florrie actually more specifically chain not Chaney chain and Florrie it was chain who was a grad student in Flora's lab so chain in 1938 came across Fleming's paper that he wrote in 1929 and he became interested in whoa wait a minute we might have something here this mold if it could inhibit the growth of Staphylococcus aureus is there more to this mold that we don't know so what he did is he decided to go ahead and purify this penicillin and when he had it pure he performed large clinical trials and guess what they were very successful but of course flurry his pee I took all the credit right okay so at the bottom of your slide it says where do most antibiotics and it got cut off but you have the slides at home where do most antibiotics come from what do you think most antibiotics come from more than half of the antibiotics produced are from are found in the soil streptomyces they inhabit a soil few of them by spore forming organisms but so as is one of the common ones or mold mostly from the general penicillin and syphilis Boreum when we're talking about molds let's go over some quick definitions here so that we can get through this chemo therapeutic agents basically drugs that kill cancer cells now selective toxicity refers to antimicrobial drugs that selects harmful microorganisms without damaging the host now that is a goal right we don't want to harm the host we don't want to the hose now here's where we get to the good stuff here synthetic drugs what are synthetic drugs so a synthetic drug is a drug whose origins are not organic and basically they're made in a lab an example of a synthetic drug would be sofa there are also semi synthetic drugs and these semi synthetic drugs are natural products that have been chemically modified in a lab for a number of reasons number one to improve the efficacy of the natural product number two to reduce side effects and number three - basically circumvent developing resistance by targeted bacteria actually to this list I can even add that some of these natural products can be chemically modified in the lab to expand the range of bacteria that can be treated with it so there is a number of reasons why semi synthetic antibiotics are a good thing taking a natural product and modifying it in the lab for a variety of reasons to improve the efficacy of the natural product to reduce any side effects circumvent developing resistance by other bacteria and to expand the range of bacteria that can be treated with the antibiotics okay and antibiotic in itself it just is the inhibition or abolishing of growth of microbial organisms features of antimicrobial drugs selective toxicity is something that we need to look at when it comes to antimicrobial action when we're talking about antibiotics we think about is this antibiotic bacteriostatic or bacterial seidel what the difference what does a mean to be bacteriostatic what does it mean to bacterials to be bactericidal bacteriostatic means that the fact that the drug whatever it is that you are using does not kill the bacteria but prevents it from or stops it from continuing to reproduce so it's just Stacey's it's like refrigeration right refrigeration is bacteriostatic it doesn't necessarily kill the bacteria it just stops it from continuing to replicate as soon as you remove whatever item is or the culture from the refrigerator then bacterial growth can continue bacterial sidle on the other hand kills the bacteria now when we're talking about Manta microbial action another thing that we need to consider is broad-spectrum antibiotics versus narrow-spectrum antibiotics and what does what does that mean a broad-spectrum antibiotic an example that I can give you for this would be an antibiotic that can be effective against gram-positive organisms as well as gram negative organisms whereas a narrow spectrum antibiotic would be an antibiotic that would only be effective against gram-negative for example so that's one of the differences or that's the difference between a broad-spectrum antibiotic and a narrow spectrum antibiotic tissue distribution and metabolism it's another thing that needs to be considered when we're talking about antimicrobial drugs what is the drug half-life how long does it take before the drug is half efficient right so that's the half-light here's an example in this table of the spectrum of activity of various antimicrobials so to give you an idea of which antibiotics would be considered broad-spectrum as opposed to narrow spectrum let's see here we see that polymyxin would you consider this a narrow spectrum or a BA a broad spectrum antibiotic narrow because this antibiotic is only effective against gram naked bacteria but when you look at original myosin tetracycline the sulfonamide you see that these are considered what do you remember what that term is that's right broad spectrum these antibiotics are effective against gram-negative gram positive even chlamydia and look at so fun Oh might it's even effective against protozoa right now maybe if there was a protozoal infection you may want to take an easel but this is an option for sure so this gives you an idea of the spectrum of activity of various antimicrobial drugs you don't need to memorize which drugs are broad-spectrum which ones our narrow spectrum okay we're gonna talk about what you should know but this is a good table anyways to have an idea effects of drug combinations so let's talk about when we combine drugs does a combination of the drug have a synergistic effect what does that mean or does they have an antagonistic effect combining drugs is tricky it can be dangerous and sometimes it's beneficial so when we talk about the drug combinations a synergy synergy or synergistic effect occurs when a drug interacts in ways that enhance or magnify one or more effects or side effects of the drug now what the heck does that even mean well I'll give you an example codeine is often mixed with acetaminophen or even ibuprofen and the reason that it's mixed is to enhance the action of coding as a pain reliever it's not necessarily because we want to treat the patient's fever the patient might not even have fever right but coding is mixed with acetaminophen to enhance the action of the coding as a pain reliever another example of synergy is in the drug called trimethoprim and so from so fomepizole it's a combination drug when you have those two drugs in combination you only need 10% of the concentration as opposed to giving just one so that's beneficial as well now what would be what would be an antagonistic combination this would involve multiple agents that would reduce the overall effect that's not a good thing so an example of this would be using penicillin and tetracycline together that's not a good combination because when you combine them they're actually less effective then if using each of those antibiotics alone there are times and many times when a patient will be on multiple antibiotics so it doesn't mean that a patient cannot take two different antibiotics at the same time you just have to be careful about the combination which two or which antibiotics are you choosing to give the patient right adverse effects are things that need to be considered especially as future health care providers allergies is a big thing that you need to be careful with toxicity of the antibiotics and suppression of normal flora antibiotics target bacteria so when a patient is on long-term antibiotics that definitely can affect the patient's normal flora and oftentimes diarrhea can occur as a result various other infections can give rise women can have yeast infections because now you're killing the normal bacterial flora of the vaginal area causing the normal flora which is yeast in that vaginal area to flourish see you break the balance so those are some of the adverse effects of taking antibiotics let's talk about microbial resistance which we know is a growing problem with various microorganism and here we talk about the intrinsic effect where the drug has actually no effect on the microbe or microorganisms can have acquired resistance and this resistance is usually due to some mutation or new genetic element and here in parentheses I have plasmid well how can a microorganism acquire plasmids do you remember how think about it that's right through conjugation that's one of the different types of horizontal gene transfer that we went over in previous lectures where one bacteria one donor bacteria will transfer or replicate its plasmid through what method do you remember what method that was rolling circle method of replication and transfer that plasmid to a recipient bacteria via the sex pillai and then there was a little bit more detail that I went over right F plus F - do you remember that good review so how can a microorganism become resistant these are the four mechanisms by which a microorganism can become resistant you should become familiar with these number one in activation of the antibiotic so there are some microorganisms that can boom inactivate the antibiotic no longer let it be viable number two alteration of the target site hmm that means that the antibiotic is designed to target a specific feature of the bacteria well guess what happens to that the bacteria changes it so is the antibiotic or new function anymore and target that no number three decrease uptake of the drug hmmm that means that the bacteria will undergo some sort of mutation to not really allow the bacteria to go in and number four increase elimination of the drug what that really means is that as quickly as antibiotic goes in it is ejected out of the bacterial cell so I have some examples there for you but let's outline them a little bit on the next slide here we see the mechanism of antimicrobial resistance which are the four that I outlined in the previous slide know normally the way that we would want our antibiotics to function and work is here you have your drug it goes into the bacteria it finds its target and boom inhibits the growth or it destroys the bacteria right so this would be considered a non resistance cell this is the way that we try to design our antibiotics however a resistance cell which can acquire resistance through a variety of methods there's a number of ways that it can happen that resistance to the antibiotic can happen so here we see drug in activating enzyme meaning that here is my drug it goes inside the bacterial cell and something that the bacteria produces in activates the drug another method or way that bacterial cells can resist anti microbials is they alter the target site so here is my drug it enters into the cell but its target site has changed it doesn't look like the top anymore do you see that this kind of reminds me a little bit of enzyme substrate interactions doesn't it okay the next way is decreased uptake so here we see that the drug it's not even able to enter the cell or if it enters it enters a very poorly and then the last way of mechanism of antimicrobial resistance is increased elimination so as quickly as the drug enters the cell it is going to be pumped out of the cell so understand those different mechanisms and the examples that I put in the other slide selective advantage of antibiotic resistance once the bacteria has this resistant and about a resistance advantage we see here depicted in this figure by all these different bacteria you can see all there DNA their genetic material and the ones that have an S represent those bacteria that are still sensitive to anti microbials okay there is however one bacteria that is resistant to whatever antimicrobial drug we're talking about here and so let's say we have this mixed culture of sensitive bacteria and one resistant bacteria we expose this culture to an antimicrobial drug and guess what happens it kills all the sensitive bacteria as it should but the resistant one survives and what do you know about the about replication bacterial replication replicates through binary fission every twenty to thirty minutes you have to for logarithmic growth and so this is how we have now a population of resistant bacteria so let's talk about some of the examples of emerging antimicrobial resistance these are some of the common the more common bacteria that we see an increase in antimicrobial resistance and here a Cox I used to be normal flora of the intestine which didn't really cause us any problem but what ended up happening now is that we see enterococci becoming vancomycin resistant hmm how did that happen well it stems back to Stef Lucas aureus Staphylococcus aureus we know is notorious for causing MRSA methicillin-resistant Staph aureus infections so a lot of the times we see this as skin infections oh but not well Staphylococcus right so what they used to do is treat with methicillin mm-hmm well Staphylococcus aureus eventually developed a resistance to methicillin oh but not to worry because we have vancomycin and so vancomycin was the antibiotic that was being used to treat these mersa cases and what do we see now we see van kamiya-san intermediate resistance to staph aureus so you know it's it's a hard one it's a definitely a very difficult one okay it is possible that because now of the overuse of ankle myosin we are finding vancomycin-resistant enterococci another one of these bacteria is streptococcus pneumoniae which causes pneumonia and invasive infections we're finding an increase in antimicrobial resistance with this bacteria another one that is well documented and very well known to have multi drug resistance is Mycobacterium tuberculosis we're going to be talking more about all of these bacteria actually when we talk about diseases later in the semester so how do we prevent and control antibiotic resistance we know that the role of physicians and healthcare workers is very important in critical and more than prescribing practices which is a big deal is patient education physicians want to make their patients happy because they know that patients have choices and so sometimes instead of doing the right thing they do the bat they do the wrong thing patients demand antibiotics because they know that they'll feel better well yes you would feel eventually because you would have felt better anyways if you had a viral infection so prescribing antibiotics when a patient has a viral infection and not a bacterial infection not a good thing right the role of patients following instructions taking the dosage as a proper times completing the entire course of antibiotics huge as soon as patients start feeling better many of them stopped taking their antibiotics well what happens when you do that you allow the bacteria to possibly mutate right to adjust to those antibiotics so that they can survive so you need to be careful you need to follow the complete course of antibiotics the role of the public understanding the limitations of antibiotics meaning and biotics are not used to treat the common cold or the flu right so those are things that we need to consider so it is important that when you are a healthcare worker that you helps patients understand the limitations of antibiotics and this concludes today's lecture