DIP Episode 33 - Antibiotics Part 3 (Antibacterials)

Okay, welcome. My name is Divine. I am a fourth-year medical student. In this episode of the Divine Intervention Podcast, this will be episode 33. We will be going over some more antibiotics. In fact, we plan to finish up all the antibacterial legions and then in a different podcast, we'll begin on the antivirals. So, we've talked about the protein synthesis inhibitors, the cell wall inhibitor. So let's go into the grab bag of other medications that constitute antibacterial. So the first group we'll talk about are the TB meds, so tuberculosis, right? Then the big thing you just want to take away is in general these drugs are hepato toxic. And the nummonic you want to remember is ripe, the R4 rifampin, the I4 isoniazid, also called INH, the P4 pairs in a mite, and the E4 ethymbutol. Now rifampin, its mechanism of action is that it inhibits RNA polymerase. And there are few of the high-yield things you want to know about rifampin. One thing is that it induces cytokrom P450, so remember rifampin revs up cytokrom P450. So the classic exam question is a lead on birth control that gets TB, and then she gets pregnant. You want to think about inducing Cp450 and increasing the metabolism of the birth control pill. Alright, rifampin also causes red secretions, right? So like you can have like red urine, like red tears, but it's totally fine. You can just go ahead and ignore that. And then it's also part of the drug regimen for leprosy, right?

And there's a nice nummonic to remember that just remember DRC, like democratic republic of Congo. So the D for the treatment of leprosy is dapsone, the R stands for rifampin, and then the C stands for clophazamine. So dapsone, rifampin, and clophazamine. Refabutin is rifampin derivative. It doesn't have many of these bad side effects that rifampin has. Now the I, so isoniazid. So the thing is there is a gene expressed in micro bacterial species called the INH-A gene. Okay, the protein product of that INH-A gene is what is believed to be inhibited by I, so niazid. People believe that that INH-A gene product is important for the synthesis of my colleague acid. And one of the things where I, so niazid is that it's a pro-drunk, so it needs to be metabolized to the active form, and enzyme known as catalyst peroxides. In fact, that catalyst peroxides is expressed by a protein known as Cpg, I mean by a gene known as Cpg. So if you understand that, isoniazid needs to be activated by the Catsg gene product, right? So catalyst peroxides to its active form, and if then inhibits the INH-A gene product, then that should tell you that you could potentially have resistance to isoniazid. If a person has a mutation in the Catsg gene or the INH-A gene. Now, another thing about isoniazid, right? You remember the crack amigos from episode I believe this was 28? We said that the I, the I there stood for isoniazid, right? So it's an inhibitor of acycromp 450.

Now, this is probably the highest yield thing to know about isoniazid is that it depletes vitamin B6. Okay? So because it depletes vitamin B6, remember B6 is pyrodoxyl phosphate, you can have some problems with that, right? So one problem you could have is a person could have is seizures. Because remember glutamate, if you want to convert glutamate, which is an excitotoxic neurotransmitter to GABA, which is a more calm down neurotransmitter, you use an enzyme known as glutamidicurboxylase. Glutamidicurboxylase actually uses vitamin B6 as a cofactor. So if you depletio vitamin B6, you have reduced GABA, and there's an increased risk of seizures. And please don't forget that antibodies against glutamidicurboxylase are associated with type 1 diabetes. Another important thing here is think about this, right? So the first step of hemicynthesis, which I believe occurs in the mitochondria, you combine glycine and succino coa to make amino level lemic acid. The enzyme that makes that reaction happen is ali synthase. Elys synthase actually uses B6 as a cofactor. So again, if a person has a depleted B6, ali synthase doesn't work, and they could have a Cedaroblastic anemia. So it's a classic side effect with isoniasid, Cedaroblastic anemia. And isoniasid also don't forget that it's a associated drug-induced lupus, right? So don't forget your antihistone antibodies. In fact, one nice harmonic for isoniasid is just remember the term INH, that's the...

The short information of isoniasid, the I should tell you that it inhibits cyatogram P450, the N should tell you that it's neurotoxic. It can cause seizures with the mechanism I described before. You can also get a peripheral neuropathy with isoniasid, because B6 is a common cofactor in many reactions that take place in neurons. And then the H for hepato toxicity. Now the next drug is pyrazinomyel, right? So the P, right? So it works well in acidic tissue. The big thing just want to know about pyrazinomyel is the mechanism of resistance is if a person has a mutation in a gene known as PNCA. Okay, so PNCA like the bank. Now a thymutol is the... the big thing you want to know about a thymutol is it causes red-green color blindness. Please go ahead and contrast this with the juxtaposition. Remember the juxtaposition is one of those cardiac medications. It's a glycoside. It's actually... it can actually cause a yellow vision. And again, if a patient is being treated for TB, go ahead and supplement vitamin B6. Okay? And if a person has latent TB on the exacts, right? Usually the right answer is to give them isoniasid for 9 months as monotherapy. And if a patient has active TB, you want to place them on the ripe regimen plus vitamin B6. But in general, they think everything in the ripe regimen for the first 2 months. And then for the last 4 months, you put them on ripe fampin and isoniasid. And as long as you have an isoniasid, you need to be placed on...

You need to be placed on vitamin B6. Okay? And last high-yield things with TB, right? For patient has HIV, remember the PPD skin test. You're looking for 5 millimeters or more of an duration. That's positive. An patient with HIV. If a patient is like a... if a person is like a med student or a healthcare worker, you want to think about 10 millimeters of an duration with the PPD skin test. A person with very few risk factors like in the US, for example, think more of 50 millimeters. 50 millimeters is positive in everyone. Another high-yield group that has 5 millimeters of an duration being positive is a person that's a close contact of a patient with TB. Okay. So the next drug class we'll talk about at a cell phone amount, right? So the thing is bacteria, they make their own folate. And the way they make folate is the convert papa to dihydrofolate using an enzyme known as dihydropthorate synthethase. And then they go from dihydrofolate to tetrahydrofolate with an enzyme known as dihydrofolate reductase. So the cell phone amounts, the way they work is that the inhibit dihydropthorate synthethase. And your dihydrofolate reductase inhibitors, I'll talk about those in a bit, but those include like your pyramethamine and your trimethoprim. Now, the thing is cell phone amounts alone. They actually back to your static.

When you combine them with a dihydrofolate reductase inhibitor, they then become back to your side up because you're blocking two sequential steps in folate synthesis and bacteria. So what are some high-yield drug names you want to know here? You want to know about so-for-methoxazole, okay? It's used to treat pneumocystis, duravetcinumonia, and HIV as a part of TMPSMX. The SMX is so-for-methoxazole. Remember your magic city phone number for perphylaxis, that's 200. And TMPSMX can also be used in toxopryphylaxis in HIV, okay? You generally begin to worry about this when the city-for-count is less than 100. But if you're already covered in pneumocystis, duravetcinum, you've automatically covered toxoplasma-gondia. Now, just an unrelated point, but I think it probably makes sense to include it here. If a person has a city-for-count less than 250, and they live in a susceptible area where they can get coxidium-micosis. Remember that shows up as spherios on microscopy. I'll go ahead and give them itchoconosol, okay? Itchoconosol, it's one of your antifongoments. And then you also want to give itchoconosol to a person that has histoplasmosis. So histoplasma-capsolata, and they live in a susceptible area. If their city-for-count is less than 150, and again, you also do make that perphylaxis with the tetrakonosol. And then don't forget that TMPSMX, right? So, again, just another high-yode use of sulfyphylaxisol.

They actually cover no cardiomein, but no cardiosol, because of those aerobic, weekly acid fast organisms. Now, sulfosol is another sulfonamide. It's actually used to treat oxidative colitis. Sofidiazine is also another sulfonamide. It's actually used to treat toxo. So if mom is pregnant and she gets a toxoplasmosis because she handled cat litter or whatever, you can actually give pyramethamine and sulfidiazine. The sulfidiazine part there is dihydroperitinthidotryl. And then the pyramethamine is a dihydrofoli reductis inhibitor. Now, remember these sulfonamides. They have sulfol in their names, right? So they can cause a sulfal allergy. And you also want to go ahead and avoid these drugs in patients with G6 PD deficiency. So the classic example question could be a person from a Mediterranean country. Takes one of these sulfonamides and then they have ready already. Think about a G6 PD deficiency in those things, right? Because these sulfonamides, they are patholoxidizing agents and they can create a lot of oxidative stress. Right? So if a person has oxidative stress and they have like a ton of hydrogen peroxide on board, you want glutathione peroxidates to break down that hydrogen peroxide to water and oxygen. But the thing is, as you're reducing that hydrogen peroxide, that's why it's a redox reaction. As you're reducing hydrogen peroxide, you're oxidizing glutathione. So if you want to regenerate, to reduce glutathione, you need an enzyme known as glutathione reductase.

And glutathione reductase uses any DPH as a cofactor. So if a person has G6 PD deficiency, remember, G6 PD is the reclimiting enzyme of the oxidative phase of the pentose phosphate pathway. A person has a G6 PD deficiency. They do not make any DPH. So they have no cofactor for glutathione reductase. So they can get into, they can, the oxidative stress can begin to damage their red blood cells. And just as an acid, we remember a person, anacenosystem is a glutathione analogue basically. So that's how we can really help in dealing with oxidative stress from like bathrooms like acetaminophen, which is converted to any PQI, that then basically explodes a person's liver. Now, your sulfonamide, another usual example presentation is in the setting of methemoglobinemia. Remember, there are two kinds of iron in hemoglobin. You can have iron in the Fe2 plus form, which is the form that can carry oxygen, or iron in the Fe3 plus form, which is the form that can not carry oxygen. So the ferrous form of iron carries oxygen. The ferric form does not carry oxygen. Now, the thing is, sulfonamides again, because they are powerful oxidizing agents, or I remember from college chemistry, an increase in oxidation number is oxidation. So if Fe2 plus is going to Fe3 plus, basically hemoglobin containing Fe3 plus iron is methemoglobin, cannot carry oxygen.

So that induction can be done by sulfonamides, so you can give meththalene blue for that, right, because there is an enzyme known as methemoglobin reductase. It reduces Fe3 plus back to Fe2 plus, and that can help you begin to carry oxygen again. But just as an aside, don't forget that Fe3 plus binds cyanide very well, okay, so if a person has cyanide poisoning, you can actually induce a methemoglobinemia by giving, immonitrate, that's another powerful oxidizing agent, it will convert the Fe2 plus to Fe3 plus, and then you give a thiosulfate, right, so that you can put that complex outer successfully. So methemoglobinemia is not always bad. Now, another higher thing with your sulfonamides, right, they can cause connectors, right, so if you think about the metabolism of hemoglobin, right, so hemoglobin is broken down first to hem and globin, that's why it's called hemoglobin, and then hem is converted to believed verdin, so you're covering hem to believed verdin by an enzyme known as hemoxygenase, and then believed verdin is converted to indirect believed verdin or uncondugated believed verdin by an enzyme known as believed verdin reductase, and then that argument carries the indirect believed verdin.

The thing is if a patient takes the sulfonamide, you actually displace that indirect believed verdin from argument, and because indirect believed verdin is lipid solubil, it's no water solubil, it's lipid solubil, it can actually cross the blood-brain barrier, deposit it in the basal ganglia, and can, and other parts of the brain in general, and it can cause connectors, that's why sulfonamides in general are weighted in newborns. Now, trimethyl, trimethyl prem, I already mentioned it inhibits dihydrofoli reductase, so you classically quadminister this with the sulfonamide. Again, it's bacterostatic as monotherapy, but when you convert, combinator with a sulfonamide, it becomes bacterosidol. Now, the thing is because this drug inhibits dihydrofoli reductase, you can actually cause a bone marrow suppression, just like methyl trexite, and remember, it can rescue under those situations with a lucovolic. Lucovolin is a folinic, not folic, folinic acid, and unlock. Now, the next drug I'll talk about is metronidazol, right? So, no one really knows how metronidazol works, but we think it generates free radicals, and you want to know the things that metronidazol covers, right? The classic mnemonic you've probably heard a million times is get gap on the metron. So, the G is for GRD, right? Remember, that's a pretty common GIA infection, especially in patients with Ig deficiency of a person, a person goes and drinks water from a stream, while they are hiking. Think about GRD with that.

The E is for intamibah, histolyrica. Remember, it causes liver abscesses, and it's the only protosyl cause of bloodied area, at least that you need to know, for exams. The T stands for trigononus, don't forget the frothy green sputum. I mean, sorry, the frothy green vaginal secretions and strawberry-colored cervix. The G stands for Gardenerilla vaginalis. Remember, the fish-yoder, pH-graded, and 4.5, and remember that you see clue cells on my cross-copy with that. And then the A's for anaerobes, classically anaerobes below the diaphragm. That's why metronidazol is a treatise for a lot of GIA infections. Together with a fluoroquino-lonal for gram-negative coverage, like C-proproxysin. And then the Pia for the protozones. And then also don't forget that metronidazol. It's actually part of quadruple therapy for H-pilory. Remember, MBTP, right? So metronidazol, bismuth, tetracycline, and a PPI. And the M there's metronidazol. And then you can also use metronidazol for C-difcolitis. Now, the thing is metronidazol can cause GI upset. Probably won't be tested to a pretty common side effect. But it can also cause a di-sol from side effect because it inhibits as a tau-dahaid dehydrogenase. This is actually not always true. But the thing I'll say is if a drug has isol in the name, it probably can cause a di-sol from side effect. Because that isol group, I believe. I have to do some more research on this. Has some rolling inhibition of as a tau-dahaid dehydrogenase.

So that's it with metronidazol. Now, the next drug I'll talk about is called the steam. This is occasionally known as polymixin B and E. These drugs, basically the way they work is they're like a cationic detergent. So because they're cations, they bind well to gram-negative organisms. They basically turn gram-negative organisms to my cells. And those gram-negatives just disappear. Just sort of think of if you're a breaking back fan. So it's like Heisenberg style, if you know what I mean. And these drugs I use again to treat really bad gram-negative infections. They're like the last of the last line, if carbapenemps, for example, I'm not working for a patient. Because there's almost actually no resistance to colistin. Although there's been some new resistance reported in the literature fairly recently. Now, these drugs are very nephrotoxic there. Many people that take these drugs are really going to renal failure. Okay. So that's it with polymixin B and E. E. K. A. colistin. So let's talk about the fluoroquino loans. The fluoroquino loans, basically the way they work is they inhibit tau-py summary, too. Another name for tau-py summary is two mission and exam is DNA gyries. Okay. DNA gyries. So tau-py summary is right. The thing is it deals with supercores that crop up as you begin to open up DNA to gain access for transcription. For example. And the thing is to relieve those supercores. The thing tau-py summary does is it causes a DNA strand break. It undoes the supercores.

And then it then re-enails the DNA back together. So the thing is the way these tau-py summary inhibitors work, the fluoroquino loans. They work by inhibiting tau-py summary after it has made the DNA strand break. If DNA, the strand has been broken and you're like, whoa, you've not fixed that strand break. That can trigger a papotosis in a cell. So that's how the fluoroquino loans actually work as a bacterial side-alagents. Because again, because it causes death of stuff, they cause the bacterial side-alagents. Now, there's a sort of like a weird trend with these fluoroquino loans. So if you think about the cephalosporins, I believe I mentioned this in that podcast. But the thing is the cephalosporins, they actually increase in gram-negative coverage as you go from an earlier generation to a later generation. And they decrease in actually decreasing gram-positive coverage as you go from an earlier generation to a later generation. That's kind of the opposite in fluoroquino loans, although with a small change. So the thing is the fluoroquino loans from generation one to like generation three or four, you actually have better coverage of gram-positives. But so generation one of the fluoroquino loans, they have like solid gram-negative coverage. They have relatively poor gram-positive coverage. But if you look at generation three and four, they have very strong gram-positive coverage. But they actually do have good gram-negative coverage as well.

So don't say, oh, as you go from Gen one to Gen four, you decrease in gram-negative coverage. That's not true. They actually have Gen four has good gram-positive and gram-negative coverage. But Gen one has primarily good gram-negative coverage. It doesn't have very good coverage of gram-positives. So some quick, high-yield things to not buy a fluoroquino loans. So you need to know drugs like CIPR Floxacin. Again, coverage of gram-negative is really well. The first generation fluoroquino loan, you can also use, it can also be used to treat pseudomonas. Remember, pseudomonas is a gram-negative organism. CIPR is also pretty good for UT Is. Although in general, TMPSMX is used for UT Is, but CIPR is not a bad idea either. But also, remember, though, if a pregnant woman has a UTI, you cannot use TMPSMX or fluoroquino loans because they are heterodoginic agents, right? In general, in pregnancy, if a lady has like cystitis, you go ahead and give her nitrofyrantone. That's the drug that's classically known as macrobid. If a lady that's pregnant has pylon of fritis, usually go for a big, dull, like, CIPR, so, members of CIPR is very good at covering gram-negatives, like E-coli, which is the most common cause of UT Is. Now, the second, actually, no, I mentioned that the most common cause of UT Is is equal. I was the second most common cause of UT Is. I hope you're thinking, staff, some prophetic us. Okay. Now, some other fluoroquino loans. We have O-floxicine. We have Moxifloxicine.

We have Gadi-floxicine. There's only one that does not follow the fluxicine mantra. That's my Le-Dixic Acid. My Le-Dixic Acid is a fluoroquino loan. I sort of think of it as the ethycranic acid of the lube diuretic, if you may. Now, again, as I said, the leader generation fluoroquino loans they cover gram-positive as well. That's why, in general, you use the leader generation fluoroquino loans to cover community acquired pneumonia. That's why Le-Dixic Acid is used quite commonly for the treatment of community acquired pneumonia because it can cover strapping more really well, which is a gram-positive. Now, some side effects of these fluoroquino loans, the big one you want to know is they can deposit in cartilage. Again, you do not give fluoroquino loans to pregnant women so that they don't cause problems with the fetus. Now, another drug I want to talk about is DAPSONE. It actually has the same mechanism of action as so from the foxes on. So, phonomide, so it inhibits dihydropathoric synthetase. It's a puba analogue. So, basically, when dihydropathoric synthetase sees DAPSONE as like, well, you look a lot like puba, but it takes on DAPSONE and then boom, it's inhibited. So, the mechanism of resistance. In fact, let me just discuss this as a class. The mechanism of resistance to the sulfonamide are that you can make more puba to outcompete the sulfonamide, right?

So, just a kind of competitive inhibition, if you may, or you can mutate dihydropathoric synthetase so that it loses the ability to bind DAPSONE or any of the kind of sulfonamide. And again, DAPSONE is a powerful oxidizing agent, right? So, again, you don't want to give this to a person that has G6 pd deficiency. Remember, the classic histologic findings in G6 pd deficiency, right? So, like the hinds, bodies, and the bite cells. And again, what is DAPSONE used for? Have already mentioned one use. You can actually use it in the treatment of leprosy. Remember, the DRC mantra, right? So, the D4 DAPSONE, the R4 rifampin and the C4 chlophazamine. And then, you can actually use DAPSONE for... So, this is one way they can try to get to an exempts. You can actually use DAPSONE for PCP-prophylaxis. Remember, in PCP-prophylaxis, right? So, the Neumocystis Jervetzy. You could use trimethoprimsol from the thoxesol. That's usually first line. But, other options. You could actually use DAPSONE for that. You could also use the drug known as pentamidine, usually it's like the air solace form. Another thing you could use is atovacone plus a clendamysin. Okay? So, very high yield to know the drugs that can be used for PCP-prophylaxis. You can use TMPSMX or DAPSONE or pentamidine or atovacone. Or atovacone plus clendamysin. So, just keep those in mind. So, I will say with this, we're pretty much done with anti-bacterials. So, in a different podcast, we'll begin to talk about the anti-viral.

So, I wish you a wonderful Sunday and God bless. See you next time.

RIPE (Rifampin, Isoniazid, Pyrazinamide, Ethambutol).

Rifampin.

Seizures and peripheral neuropathy (due to reduced GABA synthesis).

Sulfonamides; G6 PD deficiency.

DRC (Dapsone, Rifampin, Clofazimine).

5 mm or more in HIV patients; 10 mm or more in healthcare workers.

It is a pro-drug that must be metabolized by catalase peroxidase, which is expressed by the Cpg gene product.

Sideroblastic anemia and drug-induced lupus erythematosus.

Topoisomerase II (or DNA gyrase).

Metronidazole (along with Bismuth, Tetracycline, and PPI).

Acute hemolytic anemia due to oxidative stress.

Trimethoprim-sulfamethoxazole (TMP-SMX) or Fluoroquinolones.

It is a pro-drug that must be metabolized by catalase peroxidase, which is expressed by the Cpg gene product.

Sideroblastic anemia and drug-induced lupus erythematosus.

Topoisomerase II (or DNA gyrase).

Metronidazole (along with Bismuth, Tetracycline, and PPI).

Acute hemolytic anemia due to oxidative stress.

Trimethoprim-sulfamethoxazole (TMP-SMX) or Fluoroquinolones.