Antibiotics: Cell Wall Synthesis Inhibitors – Pharmacology | Lecturio



welcome to pharmacology by lecture II Oh my name is dr. Provine Shukla let's talk about some antibacterial agents that we use commonly in practice now when we talk about antibacterial agents we have a very large spectrum of medications let's start off with cell wall synthesis inhibitors these include the penicillins the cephalosporins the carbapenems and other miscellaneous drugs when we take a look at these agents there's there's quite a large variety within each subgroup with the penicillins we have penicillin a susceptible and penicillin pal penicillin is resistant agents within the cephalosporins we have first second third fourth and fifth generation of cephalosporins carbapenems are a relatively new group of drugs that have come onto the market recently and then we have miscellaneous drugs these can include us tree Anam and vancomycin let's start off with the penicillins so remember that penicillins are active on the cell wall now the cell walls you can see them here they have sites that are amenable that are amenable to transpeptidase this allows cross-linking of the components of the wall and when you have cross-linking you have a stronger wall now cross-linking is created or facilitated by proteins that act on those peptidoglycan zuv the cell wall and links them together much like a zipper does penicillins have a beta-lactam ring that binds to that protein and for this reason the proteins are called penicillin binding proteins so a penicillin bright binding protein is where the penicillin is going to be active now if you inhibit the penicillin binding protein Auto catalysis of the cell wall will occur in the cell wall will break down now the bacteria have developed defense mechanisms against the penicillins so some bacteria have beta lactamase enzymes they're also called penicillin eases in other parts of the world now these beta-lactam ease break down that beta-lactam ring this is the mechanism of most types of resistance and they're countered by the inhibitors of these enzymes so clavulanic acid is an agent that inhibits the beta lactamase now we use that in combination with amoxicillin and we sell it as amoxicillin clavulanic sub lac Dam is another beta lactamase and we sometimes combine that particular agent with ampicillin and we sell ampicillin sub seblak dem & Tazo back Tam is the third one and for example we'll combine it with PIP Ursuline as pip Tazo now there are other mechanisms of resistance that bacteria will have against penicillin sometimes there's actually a structural change in the penicillin binding protein which renders immunity or resistance to penicillin this is actually the mechanism of methicillin resistance and it's become a real problem in our hospitals sometimes there's actually a change in the pauran structure of the outer wall so for example the resistance of Pseudomonas to penicillins is a great example the penicillin isn't able to penetrate because there's a change in the pouran now we'll talk about some narrow spectrum penicillins that are out there methicillin AFSA sill and an ox oxacillin our narrow spectrum agents they're not used much anymore I remember when we started medicine we used to use methicillin all the time methicillin-resistant staphylococcus has essentially taken methicillin off the table in terms of our choice because the these mr essays are resistant to all penicillins methicillin is also linked to interstitial nephritis nafs asil and is associated with neutropenia so these agents are falling out of favor but they'd still do show up on our susceptibility charts now ampicillin and amoxicillin you're probably quite familiar with in fact I would bet that at least some of you have been on these medications yourselves these are wide spectrum age but they are still susceptible to beta lactam Aizaz they are enhanced when combined with Clavel innate and an int arrow care in enteric aqua infections ampicillin is complementary with amino glycosides so in enteric aqua infections we will often use combinations like ampicillin gentamicin because they work very well together that's called bacterial synergy and I'm going to mention it again when I talk about gentamicin pip Ursuline and Tyco Ursuline are stronger ages these are very strong agents against gram negative organisms and once again they are very complementary with amino glycosides so pip Ursuline for example will be combined with tobramycin to give a very strong gram-negative treatment once again these drugs are susceptible to the penicillin aces so we often combine drugs like pepper salinities herb öktem to limit the resistance let's talk about cephalosporins now we divide the cephalosporins into first second third and fourth generation and in general the first generation are more gram positive active and the fourth generation tend to be more gram-negative and there's a spectrum in between now cefazolin and cefalexin are first generation agents they're gram positive active and they're very useful in surgical infections because a lot of surgical infections come from staph aureus and other skin surface agents there's minimal effectiveness of these drugs against gram-negative bacteria the second generations the prototypical agent is Sefo t10 they are much more active against gram-negative and what's interesting as they'll often work again also work against Hamas influenza which is one of the major causes of pneumonia in many of our patients other agents are in this group includes cefuroxime now if you notice very carefully I've underlined two of the agents I've underlined Sefo t10 and I underlined cefuroxime these are the drugs you need to know cefuroxime is commonly used in pneumonia treatment the third-generation agents are more gram-negative active once again I've underlined two of them cefotaxime and ceftriaxone cefotaxime is kind of our go-to drug it's a very very good gram-negative agent it will often work against organisms that are resistant to penicillin we only use these drugs in serious infections and in general they're only available in intravenous form let's move on to the fourth generation cephalosporins so cefepime is your prototypical agent and notice that I've underlined it because it's a drug that I want you to know these are more resistant to the beta lactam Aizaz and they're also active against Enterobacter hemolysis and Neisseria SEF terylene has activity and infections caused by methicillin-resistant staphylococcus so we sometimes use it in that case now remember that the cephalosporins are less likely to cause rashes and allergic reactions when compared to the penicillins penicillin seems to be associated quite heavily with rash and other allergic activity there are two new fifth generation cephalosporins called SEF – rollin and SEF Toby Pro please note that sceptre rollin used to be called an unclassified cephalosporin I mentioned it in the fourth generation segment these drugs are not yet available in all countries the definition of the fifth generation is not agreed upon by all countries but in the USA it is commonly accepted these drugs are similar to the third-generation cephalosporins with respect to a broad spectrum activity against gram-negative bacteria they are as good as the third-generation cephalosporins in this regard they have activity against gram-positive bacteria including mrs a as good as vancomycin or as tree onnum septa Rowland is approved for use in community acquired pneumonia and skin and skin structure infections septa by parole binds to PBP to be in mrs a it is approved for use in hospital acquired pneumonia and community acquired pneumonia it is an intravenous drug only other beta-lactam drugs include s tree mm now this is not commonly used in clinical practice and you don't hear much about it it is a drug that you need to know why because it's resistant to beta lactam Aizaz which is huge there is no activity against gram-positive drugs with this particular agent it binds to penicillin binding protein type 3 or PB P 3 the half-life is prolonged in renal failure so you can adjust your medication accordingly adverse events include GI upset vertigo headache but the nice thing is is once again it's resistant to beta lactam Aizaz and there's no cross allergy with the penicillins let's move on to the carbapenems so these are the kind of guerilla sillens we like to call them they're very very powerful agents the prototypical agent is imipenem and there are new ones out like meropenem that are taking over you notice that I've underlined imipenem and Mir Panem these are chemically unique but still containing a beta-lactam ring they have low susceptibility to the penicillin aces they are very susceptible to renal D D hydro peptidases though so you are going to be administering them with Scylla statin which is an inhibitor of that particular enzyme they have a wide-ranging activity against gram positives gram negatives anaerobes and most importantly against Pseudomonas also a sign of actor species are very responsive to carbapenems so remember that sometimes we have a sign of a cure type infections in endocarditis so we we use it certainly in that regard let's talk about vancomycin so vancomycin is kind of an interesting one it it binds to a bacterial glycoprotein on the alanine surface of the peptidoglycan so we've kind of magnified the peptidoglycan here it the resistant organisms to vancomycin have an Alton altered terminal so there's a decreased affinity for the vancomycin in this case the vancomycin is the yellow little star-shaped thing that you see there we only use vancomycin for very serious infections now vancomycin despite the fact that we've magnified things and it looks like a small molecule it's actually quite a large molecule and it does not cross the blood-brain barrier so if you have say a spinal infection or a brain infection we administer it intrathecally we use it orally however for luminal infections of the gut because it's not absorbed across the gut wall so it stays inside the gut and if you have an infection inside the gut it's it's quite effective the important toxicity that I want you to remember with vancomycin and that I guarantee you'll be tested on is something called red man syndrome this somewhat sexist term applies equally to men and women by the way it causes severe cutaneous flushing from histamine release so it's it's quite a dramatic and quite noticeable sort of reaction and at first you think it's a it's a type of horrible allergy it's not quite an allergy in the same sense it's actually a histamine release it can also cause phlebitis ototoxicity and nephrotoxicity so this is a potentially toxic agent let's talk a little bit about bacitracin it's not often covered in antibiotic lectures because we tend to forget about it but it's it's it's used tremendously in hospitals it's used as a topical treatment and decontamination treatment for things like methicillin-resistant Staph aureus so you'll often see patients being treated with bacitracin in hospital it's used in Staphylococcus colonization of the skin now it can cause nephrotoxicity so it's not used orally or parentally we only use it topically from prep for practical purposes daptomycin is a cyclic like a lipopeptide it is for the treatment of vancomycin-resistant enterococci and vancomycin resistant Staphylococcus aureus you have to monitor creatinine levels very closely sorry CK levels very closely during treatment and that's because daptomycin is very myopic and so it can cause severe muscle disease you

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