Antifungals

0:07what's up ninja nerds in this video

0:08today we're going to be talking about

0:09antifungals as i've said before with the

0:11antibiotics antivirus lots to cover not

0:13as much as when we talk about

0:14antibiotics and antivirals but it's

0:16still important it's a pretty cool topic

0:17that being anti-fungals go to our

0:19website down below the description link

0:21in the description box below go check

0:22that out we'll have some really awesome

0:23illustrations some great notes for you

0:24guys to follow along with me during this

0:26lecture so let's start off first when we

0:28talk about antifungals how do they work

0:30so we have a fungal cell here

0:32a lot of these drugs they have a very

0:34very interesting mechanism of action and

0:36it's actually straightforward so

0:38we talk about these we're gonna talk

0:39about these top three then we'll sit

0:40down we'll come talk about the bottom

0:41three down here but

0:43generally there's a couple drugs one of

0:45the first ones that i want you guys to

0:46remember is you know inside of our

0:47actual fungi they have a nucleus in

0:50order for the nucleus to be able to

0:51undergo the division process for the

0:53fungal cell to divide make more fungal

0:55cells it utilizes these things here

0:57called microtubules so you see these

0:59things right here

1:00these guys right here are called your

1:02microtubules now microtubules are

1:04obviously super crucial to the cell

1:06division process what if i had a

1:09particular drug that can bind onto the

1:11tubulin proteins that make up the

1:12microtubules and inhibit it from being

1:15able to allow for the cell division of

1:17fungi to occur that'd be pretty

1:18interesting right and that would be a

1:19good antifungal we have a drug that's

1:21called gristiofulvin so griseofolvin

1:24will actually bind to the tubulins in

1:26the microtubules and inhibit the

1:28microtubule function and what will this

1:30lead to this will lead to decreased

1:33cell

1:34division so the fungal cell will not be

1:37able to divide so that's one particular

1:39drug so i want you to remember gracious

1:40inhibits the

1:42microtubules by preventing cell division

1:44it binds to the tubulin proteins and

1:46inhibits the microtubular function boom

1:48chrysiofolvin done all right flucitasine

1:50this one's a little interesting a little

1:52funky a little weird but it's a cool

1:54anti-metabolite drug so how this drug

1:56works is

1:58inside the nucleus of the fungal cell we

2:00have dna right dna is obviously

2:02responsible for being able to what is

2:04this called if you take dna

2:06and you make more of the dna that's

2:08called

2:08dna replication right so we take dna

2:11make dna but if we take dna we make

2:13rna so a single stranded that we're

2:15going to utilize to make proteins this

2:17is called transcription so flu cytosine

2:21is an interesting drug so what happens

2:22is flucitan gets taken up into the

2:24fungal cell when it gets taken up into

2:26the fungal cell it gets acted on by an

2:28enzyme here i don't want you to work too

2:29much to remember this one i'm going to

2:30abbreviate it it's called cytosine

2:33deaminase

2:35what cytosine dminase does is is it

2:37actually converts flucytosine into a

2:40drug called

2:425-fluorouracil fu don't get your minds

2:44clear so what happens is

2:465-fluorouracil is a very interesting

2:48drug or metabolite here where it can

2:51actually bind to specific components of

2:53the nucleic acids and inhibit them from

2:55being able to function properly so

2:57subsequently it will inhibit dna

2:59replication and it will inhibit dna

3:02transcription to make rna if you can't

3:04replicate dna will the actual fungal

3:06cell be able to divide and pass on its

3:08nuclear machinery will it be able to

3:09make fungal proteins that are essential

3:11to its function no so flucitosine would

3:14be able to again

3:15inhibit dna replication and dna

3:18transcription by

3:20being converted into a metabolite called

3:225-fluorouracil 5-fu

3:24and then inhibiting that type of

3:26function so that's one of the other

3:27drugs flucidasine

3:28all right boom roasted next one is

3:31echinocannons now econo cannons are a

3:33really cool drug category so when we

3:35talk about these there's actually um a

3:37couple different ones if you really

3:39can't remember the names of them that's

3:41okay i want you to remember that echino

3:43cannons always end in fungi pretty

3:46original right so fungi so two big ones

3:48that you'll probably see microfunction

3:50this is the one that i have at my shop

3:51at the hospital and then there's another

3:53one called caspofungen there's also

3:55another one

3:57as well but these are probably gonna be

3:58the most commonly two utilized fungions

4:00that you'll see are the echino

4:01candidates now these drugs are really

4:02interesting you know you see this cute

4:04little enzyme here this little bird

4:05enzyme this guy here

4:07is called a beta

4:09one

4:10three

4:11glucan

4:12synthase you're like what the

4:15this cool little dude right here what he

4:17does is he takes specific types of like

4:19carbohydrate molecules

4:22and converts them into a molecule called

4:24beta

4:26one three glucan i bet you couldn't

4:29figure that out by the name of this

4:31enzyme name but what it does it actually

4:33takes and makes these particular

4:34molecules called beta one three glucans

4:36and there's other components here in the

4:38cell wall beta one six glucan but this

4:41structure here is integral to the actual

4:43cell wall and what do we know about cell

4:45walls cell walls are supposed to provide

4:47you know in general in this fungi

4:49resistance to osmotic forces so

4:52generally

4:53if it's providing good resistance to the

4:55osmotic forces imagine i give a drug

4:57called echinocanus what do you think

4:58it's going to do

5:00it's going to inhibit

5:02this beta 1-3 glucan synthase will it be

5:05able to take carbohydrate molecules and

5:07incorporate into 3 beta-1-3-glucan to

5:09incorporate into the cell wall no so we

5:12have a decrease in the beta 1 3 glucan

5:14and the cell wall activity will now be

5:17hindered because there's now going to be

5:19decreased resistance

5:22to

5:24osmotic forces and this this this this

5:26fungal cells all kinds of jacked up then

5:28it's going to end up undergoing cell

5:30death by cell lysis processes

5:32so that's this type of drug category so

5:34so far we have gracious inhibits the

5:35microtubules right we have flucytosin

5:38forms a metabolite called 5fu which

5:39inhibits dna and dna replication and dna

5:42transcription and then we have the kind

5:44of cannons the fungi microfungus and

5:45gastrofunction which inhibit the beta 1

5:473 glucan synthase inhibiting the glucan

5:50molecules that are important to the cell

5:51wall

5:52resisting osmotic forces now you get rid

5:54of that you don't have strength against

5:56osmotic forces boom the cell can

5:57actually undergo lysis and die all right

5:59we're not done now we've got to come on

6:01to these bottom three drugs here and

6:02talk about them all right so the next

6:04thing when we talk about this next drug

6:05called terbenaphine it's actually pretty

6:06cool but we have to go through a little

6:07pathway so

6:08when we talk about the pathway within

6:10the side of the fungi there's a very

6:11important component here see these like

6:12green structures here it's called

6:13ergosterol let's actually write that up

6:15so this molecule here is called

6:16ergosterol

6:17so er

6:19gasterol

6:21now ergosterol is kind of like a

6:22cholesterol molecule if you will it's a

6:25so what happens is in order for us to be

6:26able to make this it first off it plays

6:28a role within the stability of the cell

6:30membrane so stability of the cell

6:31membrane is the primary function of our

6:32gastro which is a cholesterolic molecule

6:34we know that generally cholesterol plays

6:36a big role in cell membrane

6:37stabilization especially with like

6:39temperature and ph changes etc so

6:42we need to make ergosterol in order to

6:44incorporate that into the cell membrane

6:46to provide stability how do we make it

6:48so you start off with a particular drug

6:50called squalene so squalene

6:53such a funny name gets acted on by a

6:55very specific enzyme called squalene

6:57epoxidase which converts squalene into

7:01what do you know squalene epoxide

7:04then squalene epoxide is then converted

7:08into another molecule called lanosterol

7:12and then linosterol is then going to be

7:15converted into

7:17ergosterol

7:19via this other enzyme and then we'll

7:21talk about that one right there all

7:22right so we have this kind of pathway

7:24here if you will so squalene to squalene

7:26epoxide is acted on but it's actually

7:29particularly this reaction occurs based

7:32upon the presence of this cute little

7:33blue enzyme what's this cute little blue

7:34enzyme called this blue enzyme here

7:37is called squalene

7:40epoxidase

7:41it's called squalene epoxidase and this

7:44drug here called terbenophene will

7:46actually inhibit the squalene

7:49epoxidase if you inhibit squalene

7:52epoxides you reduce the conversion of

7:55squalene to squalene epoxide then if you

7:58reduce the production of squalene

8:00epoxide you don't make as much

8:01linosterol if you don't make as much

8:03lanosterol you don't have as much

8:04ergosterol if you don't have ergosterol

8:07you have decreased stabilization of the

8:08cell membrane therefore it's at risk of

8:11the fungal self dying

8:13that's an important process here so

8:15terbenaphine inhibits the squalene

8:17epoxidase inhibiting ergosterol

8:19synthesis important for cell membrane

8:22synthesis so so far we've got

8:24graciofulvin microtubules flucyitosine

8:26inhibits dna and rna synthesis

8:28echinocannons inhibits beta one gluco

8:31three glucan synthase and then

8:33terbenaphine inhibits squalene oxidase

8:35okay we got another one obviously it's

8:37this cute little guy here

8:39this one here it's got a heck of a name

8:41so we had all this space here it's

8:43called and it's specifically going to

8:45stimulate this particular process this

8:48is called the cyp 450

8:5114 alpha

8:54d-methylase oh my gosh that's such a

8:56long name but this enzyme is responsible

8:59for converting linosterol into

9:01ergosterol so if i give a particular set

9:05of drugs called azoles the azoles will

9:08inhibit the

9:10cyp45014 alpha dimethylase which is

9:13basically going to reduce the conversion

9:16of linosterol into ergosterol if there's

9:19lesser gastro there's less stabilization

9:21of the cell membrane and more likely for

9:23the cell to be able to die

9:26that is the process of these two drugs

9:28so if you want to know for the actual

9:29synthesis of our gastro there's two

9:31drugs one inhibit squealing epoxidase

9:33that's trabinophene one inhibits the

9:35other enzymes cyp 450 14 alpha

9:37dimethylase that's your azoles now

9:40azol's there's a couple of these drugs

9:42one is called your triazoles and one is

9:44the amidazoles

9:46okay with these your triazoles are very

9:49potent very powerful drugs so you can

9:52remember what's called avoriconazole

9:55as one of these you can remember what's

9:58called itra conazole

10:01for this one and you can remember isa

10:04vueconazole

10:06these are very very powerful drugs

10:08another one here is called posaconazole

10:11this one we don't see too much it may be

10:13used in like prophylaxis in certain

10:14situations but this last one here is

10:17another big one that you guys have

10:18probably heard it's called fluconazole

10:20fluconazole so these are your triazole

10:23so your triazoles

10:25are going to be voriconazol itraconazole

10:27isovuconazole posaconazole and

10:29fluconazole

10:31for the imidazoles these are less of

10:33those potent agents and this is going to

10:35be something called

10:37myconazole

10:40clotrimozole

10:43and the last one here is called

10:45ketoconazole

10:48all right and we'll talk about all the

10:49functions like which ones what kind of

10:51infections does these cover versus what

10:53these cover and etc with all of these

10:54but i just want you to have an idea

10:55about the actual azole's mechanism of

10:57action okay we got the mechanism of

10:59action done now we know that these are

11:01inhibiting the argosterol synthesis

11:03which is important for cell membrane

11:04stabilization

11:06there's one last drug category here and

11:09these are called polyenes now polyes are

11:11very very interesting so if we take a

11:14look let's say that we actually zoom in

11:16on the cell membrane at this level here

11:18so what we're going to do is we're going

11:19to take this kind of portion here and

11:21we're going to zoom in on it really

11:23really well and we see here we have our

11:24cell membrane so all of this component

11:26here is going to be the

11:27inner cell membrane of the actual fungus

11:31and then here we're going to have our

11:33gastro molecules here here's our gastro

11:35molecules in green

11:37what happens is is you have this drug

11:39which are called your polyenes polyes

11:41are really cool because what they can do

11:42is they have two different types of like

11:44surfaces on them if you will one of the

11:47surfaces

11:48is going to have a surface where it can

11:50actually bind to

11:52lipid molecules so one surface is

11:54actually going to be loving to bind to

11:56the lipids so it's the lipophilic

11:57surface the other surface of this

11:59molecule actually wouldn't mind

12:01interacting with water and other kinds

12:03like water soluble molecules so it's

12:05more of a hydrophilic molecule so

12:07because of that it binds kind of

12:09perfectly like this so this lipophilic

12:12end here kind of like draw like this

12:14is going to bind perfectly with this

12:16green or gastro molecule

12:19and it's going to do something like this

12:20look at this so here's the lipophilic

12:22end and then here's going to be the

12:23hydrophilic on the other side same thing

12:25here's another one of these actual

12:26molecules here are polyenes one surface

12:29is going to love to bind to the actual

12:31gastro because it's lipophilic and the

12:33other one doesn't mind interacting with

12:35water molecules so that's going to be

12:36your hydrophilic end and it's going to

12:38look like this

12:40now if you kind of imagine what this

12:42does this makes kind of an interesting

12:43like type of pore molecule and it puts

12:46it into the cell membrane so now i have

12:48a pore inside of the fungal cell

12:50membrane the problem with that is that

12:52now i can have different types of ions

12:55moving in and out

12:57of this actual fungal cell causing a lot

12:59of electrolyte imbalances and increasing

13:01cell lysis and subsequent cell death

13:04so what are the drugs that actually can

13:05form these pores inside of the actual

13:07fungal cell membrane causing electrolyte

13:09disturbances because one side of it

13:11combined with the ergosterol the other

13:12side can interact with water these are

13:14your palines and there's two particular

13:16drugs here one is called amphotericin b

13:23and the other one here is called

13:25nestatin

13:26and again we're going to talk about all

13:28these actual drugs and what kind of like

13:30functions they have now that we talked

13:31about the mechanism of action let's move

13:33into what are the clinical usages all

13:34right so now we're going to talk about

13:35the clinical usages of these antifungals

13:37so there's a lot of different fungal

13:38infections that we'll go over

13:40and we'll kind of go over like which

13:41particular areas that you see these

13:43types of fungal infections in we're not

13:45going to go crazy crazy in detail

13:46because we'll cover these fungal

13:48infections like each one specifically

13:50like candidiasis and aspergillus in like

13:51the actual infectious disease section

13:53but for right now let's say you have a

13:55patient who has candidiasis and it

13:57depends upon where the actual candida

13:58infection is to determine which

14:00antifungal we will pick if it's in the

14:02oral cavity or near the fence they have

14:04like the oral thrust or they have some

14:05candidiasis near the actual pharynx or

14:07tonsils what are you giving them

14:09generally nestatin tends to be the

14:10actual preferred agent now nestatin is

14:12super super powerful if you give it

14:15intravenously so we cannot give it

14:16intravenously so generally it's more of

14:18a topical agent

14:20or you can actually put it in the mouth

14:21swish it up and then swallow generally

14:23that's going to be the preferred

14:24function here in oropharyngeal

14:26candidiasis so we can do nestatin but

14:28it's important to remember that this is

14:30not going to be an oral in the stat it's

14:31not going to be an intravenous it's

14:33generally going to be this is no joke we

14:35actually say swish

14:36and swallow

14:38for the actual nastatin the second agent

14:40that we can also use is clotrimozole but

14:42particularly it's like a lawson so it's

14:44not really an oral like agent it's

14:45actually more of a lawsuit that we can

14:47have the patient kind of have and like

14:48dissolve over time so the other agent

14:50that you could utilize and chloramizol

14:52which one was that was that the actual

14:53amidazole or the triazoles it was the

14:56imidazole along with meconazole and

14:57ketoconazole so clotrimazole

15:00would be the other agent here that you

15:02could utilize and this is going to be

15:04like in a lozenge kind of form

15:06so these would be the two agents that we

15:07utilize for oropharyngeal candidizes now

15:10let's say that actually gets into the

15:11esophagus if it gets into the esophagus

15:13and start causing like esophageal

15:14lesions there what do we do for this one

15:16this one's generally oral fluconazole or

15:19itraconazole that's one of your

15:21triazoles so in this one we can do

15:24fluconazole

15:26or we can do something called

15:28itraconazole but it's important to

15:30remember for these ones we need a little

15:31bit more systemic involvement so these

15:33are both going to be

15:34po oral okay

15:36next one is volvo vaginal candidiasis so

15:39if someone develops a nasty vocal

15:40vaginal candidiasis what do we utilize

15:42for this one so you start off with

15:44topical azoles and this is not the

15:47triazoles this is the topical imidazoles

15:50so topical

15:52would be the preferred

15:53type here for meconazole

15:58or clutromazol so you try this as the

16:01first line agent if they do not respond

16:04to that then you do something called

16:06fluconazole so this is going to be po

16:09and if they don't respond to that you

16:11could add on that drug called

16:13flucitosine do you remember what flu

16:15cytosine did so cytosine was that 5fu

16:17molecule inhibits the dna rna type of

16:19activity whereas the azoles are

16:21inhibiting d c y p 450 14 alpha

16:24dimethylase and then the statin is the

16:26polyene forms the pores just trying to

16:28see if we can go back and remember these

16:30things all right so we got oropharyngeal

16:32esophageal volvo vaginas what about

16:34intertrigonous type of candida

16:36infections this is where you have very

16:37very moist areas where sometimes that

16:40moisture can allow for candida to kind

16:41of just thrive in generally this is the

16:43axillary and the anal genital area so in

16:46the axillary or the anal general area

16:48where there's lots of moisture this can

16:50be an area where candida can thrive and

16:53generally nestatin as a topical agent

16:57would be the preferred type of agent

16:59that we would utilize in this infection

17:00for intertriginous candida so so far

17:02we've covered oropharyngeal we've

17:05covered esophageal

17:06we've covered volvo vaginal and the last

17:08one here or the almost last one is the

17:10intertrigonous one we now need to talk

17:12about the worst case scenario what if

17:14the candida gets into the bloodstream

17:16becomes more systemic or causes a lot of

17:18a deep infections that are not

17:21mucocutaneous in that situation we're

17:23getting into candidemia candiduria what

17:26do we do for that let's come down and

17:27talk about that if you have a patient

17:29who has systemic candidiasis there's

17:30likely generally in most fungal

17:32infections like systemic fungal

17:33infections there's likely

17:34immunosuppressed in some way so

17:36transplant hiv have severe diabetes

17:39something that's really making their

17:40immune system severely depressed that

17:42allows for these kinds of fungi to cause

17:44nasty infections if a patient ends up

17:46with like nasty systemic infections so

17:47they have like for example candida

17:49causes like endocarditis and that's a

17:51possibility sometimes you can see

17:53endocarditis or you see like really

17:56nasty like bloodstream infections

17:58another one is uti so genital urinary

18:00candida or believe it or not ocular

18:03candidiasis you can actually get

18:04infections of the eye with candida so

18:07some type of ocular involvement but i

18:10think the big thing is that it's

18:11disseminated it's in it's used the term

18:13maybe systemic or invasive

18:15it's really starting to involve other

18:17organs and it's not just at the skin

18:19level now it's actually gotten to the

18:20bloodstream and spread to other areas or

18:22it's involving deeper organs

18:24in those situations the preferred first

18:27line agent is echinocandins do you

18:30remember the echino cannons the

18:31echinocannons was your funjins

18:34this was your microfungan your casper

18:36fungi what did it do it inhibited the

18:38beta-13 glucan synthase i know you guys

18:39knew that but let's actually put that

18:41this is the first line

18:44other agents that you can consider as an

18:46add-on it just doesn't cover all the

18:47candida species it covers a good chunk

18:49of them though is fluconazole

18:52and again this has to be po

18:54and then the other one would be

18:56amphotericin b so amphotericin b is

18:59another potential option here sometimes

19:01they will say that you should add on

19:02another agent like flucytosin to that

19:04one but generally amphotericism would

19:06kind of be the last line so generally

19:08you'll start off with of echinocannons

19:09first line if that doesn't work

19:10fluconazole and then generally

19:12amphotericin but again important to

19:14remember here for the systemic invasive

19:16infections if somebody says which one do

19:17you treat with first it's always

19:19echinocannon so i would actually try to

19:21remember that one significantly

19:23fluconazole would be kind of your second

19:24line agent amphoterible or amphotericin

19:27would be kind of like the last line for

19:28these all right we talked about

19:29candidiasis let's now move into the

19:30other fungal infections all right so

19:32let's talk about aspergillus so this is

19:33an interesting type of like mold

19:35infection so when we talk about

19:36aspergillus it really tends to

19:37particularly involve the lungs all right

19:39so primarily the respiratory system it

19:41starts off kind of like causing like a

19:42little bit of like a pneumonitis or like

19:44a bronchopulmonary like involvement but

19:46then it can actually cause the trachea

19:47and really cause like a necrotizing

19:49tracheitis then extend down and if

19:51somebody prior had like a tb and they

19:53had a cavity here from the tb the actual

19:55fungus can hop into that and cause like

19:57a really nasty like fungal infection

19:58there almost like a fungal ball not even

20:00kidding it's called an aspergilloma and

20:02sometimes from here it can actually

20:03disseminate so it can really really

20:04cause the lungs to wreak a lot of havoc

20:06on the lungs so in general when somebody

20:08has some type of aspergillus infection

20:10we treat them very very intensely for

20:12invasive aspergillosis

20:14so preferably the first-line agent in

20:17aspergillus is going to be voriconazole

20:20so voryconazole will always be the

20:22answer

20:24as the first line agent second one would

20:27be the isovuconazole

20:29you could consider that one

20:31if they can't take the voriconazole for

20:33some particular reason another agent is

20:36echinocannons echinocannons are also

20:38very very good at covering your invasive

20:41aspergillosis the last one i would say

20:43would be really like if you really need

20:45to because the refractory to all the

20:46above things would be your amphotericin

20:49but that would be pretty much your last

20:50line so i would actually remember your

20:53voriconazole first line isobiconazole

20:55also has some pretty good coverage and

20:56then the kind of cannons last one for

20:58severe refractory cases you can consider

21:00amphotericin be the next one here is

21:02cryptococcus it's kind of like a yeast

21:04like species if you will

21:05and it really loves to kind of harvest

21:07hair in the lungs and cause a lot of

21:08like pneumonia but it also can spread to

21:10the meninges and cause a really nasty

21:12cryptococcal meningitis so whenever

21:14we're covering cryptococcus is a

21:16two-part therapy there's the induction

21:18kind of like the first two weeks that

21:20someone's actually been diagnosed with

21:21so in the first two weeks

21:23of diagnosis we actually do a two-part

21:25combo we do amphotericin b

21:28and then we add on here what's called

21:31flu cytosine so we do this for the first

21:34two weeks then after that as a

21:36maintenance therapy after those two

21:38weeks we then can keep them on something

21:41called fluconazole so then it'll just be

21:44fluconazole and we'll drop the

21:45amphotericin b and drop the flucidacy

21:49all right so that'd be cryptococcus so

21:50we so far we got aspergillus we got

21:51cryptococcus and we covered all the

21:53candidiasis let's come down talk about

21:55our endemic fungi and then we'll talk

21:56about the really nasty mucomicosis and

21:58then some dermatophyte infections all

22:00right so the next one blastomycosis

22:02histoplasmosis coccidiomycosis

22:06generally these are endemics so they're

22:07dependent upon the geographical area

22:09that's a little bit beyond the scope so

22:10we're not going to go into that i would

22:12just want you to know if you have a

22:13patient in their vignette they're

22:14diagnosed with blastomycosis or

22:16histoplasmosis or carcinoicosis these

22:18can involve

22:19tons of organs

22:21so generally they most of them at least

22:2370 of the time always are going to cause

22:25some type of pneumonia involvement

22:27they may even cause some type of

22:29meningeal involvement especially histo

22:31in the coccidio you can see a lot of

22:33skin kind of involvement a lot of like

22:35skin and bone lesions particularly in

22:37blasto and histo as well so either way

22:39you can see a lot of different types of

22:40involvement primarily always involve the

22:42lungs some type of meningeal involvement

22:44and skin and bone lesions in these

22:46situations if the patient comes back

22:48positive for these particular type of

22:49fungi how do we treat them the preferred

22:52agent some of the evidence is saying

22:54that itraconazole may be superior

22:57but another drug that you could utilize

23:00is fluconazole so if you have an option

23:03between these two i would actually go

23:04with itraconazole it's actually believed

23:05to be more superior than fluconazole but

23:08fluconazole is also a decent option all

23:09right if these two particular drugs

23:11aren't available or first more

23:12specifically if you have a severe

23:14refractory case of blasto histo or

23:16coccidio you can consider amphotericin b

23:19but this would be let's actually put

23:20this down ampho terrace and b would be

23:23more for severe

23:25kind of refractory cases really

23:28but the preferred agent remember it

23:30console so again aspergillus vorticon is

23:32all crypto two part ampho flucidazine

23:35then fluconazole

23:36blastohistococcidio itraconazole first

23:39line

23:40and then you can consider fluconazole

23:41ampho if it's severe

23:43the last one here is mucormycosis so

23:46this is a type of mold and it's a really

23:48really nasty one i actually would think

23:51that you guys should remember that you

23:52can see this particularly in patients

23:53who have diabetes especially if they

23:55have like a diabetic ketoacidosis

23:57so whenever a patient has diabetes

23:59mellitus they definitely have like a

24:01little bit of immunosuppression and this

24:03actual kind of mold can cause a lot of

24:04infections of the sinuses that can

24:06actually sometimes extend up into the

24:08actual brain tissue it's going to cause

24:10kind of like a really nasty rhino

24:11cerebral sinusitis okay so you can get a

24:13really nasty type of sinusitis here they

24:16can actually cause black escars to form

24:18within the tissue sometimes you have to

24:20debride so really nasty sinusitis and

24:22then sometimes it can even spread into

24:24the actual lung tissue and cause a

24:25pretty bad pneumonia so if somebody has

24:27much or mycosis look for a patient who

24:29has diabetes in the clinical vignette

24:30look for really nasty black escarg like

24:33sinusitis also look for pneumonia

24:35involvement what do you use to treat

24:36these patients generally

24:39iso vuconazole

24:42is going to be the first line agent

24:45if that one isn't available you can

24:47consider or they don't they have some

24:50type of contraindication to getting an

24:51azole like a severe hepatotoxicity of

24:54some particular region you can consider

24:56amphotericin b

24:58if there is some particular

24:59contraindication to the above here but

25:02oftentimes because of these nasty like

25:04infectious lesions you also sometimes

25:06have to debride the lesions as well so

25:09i'd also don't forget it's not it's a

25:11little bit beyond this lecture but just

25:12remember that that's not the only

25:14treatment is the antifungals sometimes

25:16you may need debridement of the actual

25:17lesions as well

25:19all right that covers these particular

25:21nasty systemic fungal infections let's

25:23kind of finish it off with the easy

25:24commonly remembered ones which is your

25:26dermatophyte infections and tina versa

25:27color all right so the next one tina

25:29versa color so these are like these

25:30hypopigmented like lesions here that you

25:32can sometimes see like on the actual

25:34body like on the trunk

25:35and generally with teeny a versa color

25:37it's always going to be a topical agent

25:38preferably

25:40you can try something like a topical

25:41azole but these would be your imidazole

25:43so ketoconazole and mechanozol tend to

25:46actually be the preferred in these

25:48situations so you would do something

25:49like atopical

25:51and with these topicals you would do

25:52something like meconazole but actually

25:55preferred seems to be ketoconazole so i

25:58would actually remember

26:01ketoconazole as the preferred agent

26:04in this condition

26:07so i kind of put like an asterisk there

26:08for that one all right teeny versus

26:10color done the last one is your

26:11dermatophyte infection so these are also

26:12your teenia infections but we don't

26:14consider teenia versacolor to be a part

26:17of this one so with the dermatophyte

26:18infections it actually depends upon

26:20where so these are like your superficial

26:22fungal infections and it depends upon

26:24where the actual infection is that

26:25determines what kind it is so really

26:27quickly if it's kind of like generally

26:29like near the head we call that teenia

26:31capitus

26:33and then if it's occurring kind of like

26:34near the uh

26:36generally like near the beard region we

26:37call it tina barbara if it's near the

26:39actual body we call that tinia corporis

26:44if it's occurring near the actual

26:46growing region we call that tinia

26:50crores

26:52if it's occurring near the actual feet

26:54region so like an athlete's foot we call

26:56that tinia

26:57pedis and the last one is if it actually

27:00involves the toenail and causes some

27:02actual a fungal infection of the toenail

27:04we have two names for it it's called

27:06tinea ungium

27:07but oftentimes you'll see onconcomicosis

27:12as the actual common name that you'll

27:14sometimes see too

27:16artenia ungium so generally these are

27:18the types of infections that we can see

27:20now with all of these regardless of

27:22which type it is tinea capitis teenio

27:24kapoor's tiny occurrence teenapedis we

27:27can treat all of these pretty much with

27:29the same particular agents so what are

27:31those agents that we would utilize for

27:32these infections so generally the

27:34preferred agents here is you start off

27:36with the topical azole

27:38so topical agents would kind of be the

27:40first thing that you would try and so

27:41this would be again

27:42your meconazole

27:46this would be the clotrimozole

27:50this would even be attempting the

27:53ketoconazole

27:56if these don't work as the first then

27:58the second thing that you can attempt to

28:00is something like a

28:03oral itraconazole so oral hydroconazole

28:06would be another particular agent here

28:08that you can try

28:10the other thing here that we can

28:12sometimes see utilized is griseofolvin

28:15so griseofulvin may also be utilized

28:17that's kind of like your last line agent

28:19though so i'd say you're topical azolez

28:22then an oral itrachonazole if that

28:24doesn't work griseofolvin the last thing

28:26is over oncomycosis for oncomycosis the

28:29only particular treatment that we see

28:31best suited for oncomycosis is something

28:34called terbenophene

28:36so this would be the only times i would

28:38actually

28:39see this drug really being utilized as

28:41terbenavine sometimes they say

28:42griseofolvin but terbenaphine is

28:45obviously way more superior than

28:46oncomycosis and compared to graciofulvin

28:49okay so so far

28:50we've covered all of the different types

28:52of fungal infections that we would use

28:54antifungals for now that we've gone

28:56through that the next thing that we have

28:57to be aware of okay we put these

28:58patients on these antifungals and they

29:01are at risk for what types of adverse

29:03effects what kind of things should i be

29:04monitoring looking for which would make

29:06me want to not pick this drug and pick

29:08another drug depending upon their

29:09clinical history and medications that

29:10they take let's talk about that all

29:12right so let's talk about the adverse

29:13effects of these antifungals so the

29:14first one is amphotericin b so we

29:16obviously use the funny little term anfo

29:18terrible just a lot of adverse effects

29:20that we've got to be careful of so one

29:21of the big things that is extremely

29:22nephrotoxic so you have to be careful

29:24monitoring the patient's creatininal

29:25function is very very critical when

29:26you're giving this medication okay so

29:28ampliturism b remember it has

29:30nephrotoxicity so you want to be

29:32monitoring the patient's renal function

29:34when they're taking this drug all right

29:36the next thing is if you give this drug

29:38it has the ability to cause a lot of

29:39inflammation and irritation to the

29:41actual blood vessels whenever you infuse

29:42it sometimes it can even cause fever and

29:44chills during the infusion of it but it

29:46can cause phlebitis

29:48so kind of inflammation and irritation

29:50of the actual

29:52blood vessel the next thing is it can

29:54actually suppress the bone marrow

29:55particularly preventing the formation of

29:58red blood cells so you may see a patient

30:00drop their red cell count when you do a

30:02repeat cbc so you may see anemia

30:05here's the other thing it also can

30:07increase the risk of arrhythmias

30:09tachyarrhythmias so particularly what it

30:11does is it actually leads to a low

30:13potassium and it also can lead to low

30:16magnesium levels and this can actually

30:18increase the qt interval and put a

30:21patient at high risk of something called

30:23torsades de points so it's important to

30:25remember here that there's nephrotoxic

30:27effects phlebitis and sometimes even

30:29fevers and chills during the infusion

30:30anemia from bone marrow suppression and

30:33lowers your kmag which can increase your

30:35qt interval and cause torsades to points

30:38all right what about terbenaphine since

30:40we're already here it can jack that

30:41liver up there's a pretty common thing

30:42that you're going to

30:43notice from a lot of these drugs other

30:45than amphoteres and b so that'd be kind

30:46of maybe one of the reasons someone has

30:48like a very acute liver failure they

30:50have terrible bumps in their lfts and

30:52you're trying to figure out okay which

30:53one should i put them on well they

30:55already have like almost acute liver

30:56failure probably shouldn't put them on

30:57some of these other drugs ample tears

30:58and be maybe a little bit of a better

31:00option but terbenaphine if you're

31:02treating somebody with oncomycosis what

31:03would turbanife potentially need to

31:05monitor you need to monitor their lft so

31:07it is have the ability to cause a paddle

31:10toxicity so you can see a bump in their

31:11lft so monitoring that while they're on

31:13the drug the other thing is it can

31:14actually cause

31:15change in taste so a decrease or loss of

31:18taste and we call this dysqueezia such a

31:22seductive like name but dysqueezia for

31:24turbinifey all right the next one here

31:25is echinocandins

31:27echinocannons are going to be your

31:29caspar fungi microfungus albemino

31:31albimonofungen and these two drugs

31:34uh those two categories of drugs

31:35particularly microphones and casper

31:36bunch are most commonly utilized are

31:38going to cause a patatoxic effect so you

31:39notice the common theme terbenaphine the

31:41kind of cannons probably all the other

31:42ones here are going to cause hepatotoxic

31:44so you're going to want to monitor their

31:45lfts during this here's the other thing

31:47echinocan is a casper fungi and

31:49microfunction when you're giving the

31:50particular drug it may activate certain

31:52mast cells in the skin and cause a

31:54release of histamines so particularly

31:57during the infusion of this drug it may

31:59cause a histamine response that causes

32:01kind of a vasodilation of the actual

32:03blood vessels near the skin which can

32:05lead to a flushing type of reaction so

32:07you may see a lot of flushing during the

32:09actual administration of these

32:11particular drugs

32:13watch the lfts and watch for any kind of

32:15flushing all right now let's come down

32:17to talk about the azole's gristiofulvin

32:18and flucide have seen adverse effects

32:20all right so next thing azoles azol so

32:22again is your amidazoles your triazoles

32:24when we talk about these drugs

32:27i just kind of focus a little bit more

32:29particularly on the triasol so

32:30especially if you're giving them

32:31systemically so fluconazole hydrocon is

32:33all isobutanosal posaconazole and

32:35voriconazole

32:37not so much the actual ketoconazoles

32:39although you can give ketoconazole

32:41orally

32:42especially in certain situations if you

32:44do give it orally you can see some more

32:46systemic side effects but usually with

32:47the topical formulation you don't see

32:49with mechanosol and chlorotramazole you

32:51don't see a lot of the adverse effects

32:52so i remember a lot of this you're

32:53particularly going to see it more with

32:54the oral agents but don't forget

32:56ketoconazole can be given po and you'll

32:58see two particular adverse effects from

33:00p.o ketoconazole so azol's in general

33:03especially the triazoles remember that

33:04it is hepatotoxic so you're going to

33:06want to watch and monitor their lfts

33:08when you put them on this drug because

33:09you can't see a bump in that here's the

33:11other thing

33:12a lot of these azoles are cyp 450

33:15inhibitors so they're sip

33:19fee for

33:20cyp450 inhibitors and so what that means

33:23is if you take a particular drug it

33:24actually metabolizes it by adding on

33:25particular molecules like glucuronate

33:27and different types of molecules to make

33:28it a little bit more polar

33:29but it's involved in drug metabolism if

33:32we give one of these azoles it actually

33:34will increase the actual concentration

33:36of the drug so you'll have an increased

33:38concentration of the actual drug so for

33:40example

33:42let's say that you're having a patient

33:43who's taking warfarin and you put them

33:45on an azole as well the azole can

33:47inhibit the cyp-450 enzyme inhibiting

33:49the metabolism of particularly the

33:51warfarin to make it a little bit more

33:52polar but it actually increases the

33:54concentration of the total drug within

33:55the bloodstream so now they're high risk

33:57of bleeding

33:58the next thing is particularly with

33:59ketoconazole it actually can cause

34:02gynecomastia so particularly

34:04ketoconazole you may see the effect of

34:06gyneco

34:09gynecomastia this is a little bit more

34:11specific to

34:12ketoconazole

34:16the other thing is it can't actually

34:17increase the risk of arrhythmia so it is

34:19slightly probogenic because it can cause

34:22low k levels and that low k levels may

34:24actually prolong the actual qt interval

34:26slightly and if you increase the qt

34:29interval slightly there is a slight

34:30increased risk of

34:31torsod points the other thing is that

34:34ketoconazole is very interesting because

34:36it is involved in in some of the steroid

34:38synthesis pathways um because of that

34:41because it has actually worked remember

34:42we said squalene to squalene epoxide and

34:44then front to the nostril and our gastro

34:45that's all making a steroid molecule or

34:47gastro well ketoconazole can actually

34:49affect some of the actual steroid

34:51synthesis within the body the same way

34:53that it works in fungi it can work in

34:54the human body and can inhibit the

34:56production of particular hormones such

34:58as like cortisol and aldosterone and so

35:00you can actually develop an adrenal

35:02insufficiency if you have p.o

35:04ketoconazole so remember that sometimes

35:06we actually use that in treatment

35:07whenever patients are making too much of

35:09those hormones

35:10so ketoconazole may cause

35:13adrenal

35:15uh insufficiency we're going to put down

35:16arrows there but i want you to remember

35:18this is particularly to

35:20ketoconazole

35:22the last one is going to be visual

35:24dysfunction so it can actually cause

35:25visual dysfunction uh visual

35:28disturbances and this is more specific

35:30because i want you to remember visual

35:31dysfunction you see the visual

35:33the

35:34voriconazole is the more particular

35:36agent v visual dysfunction voriconazole

35:39is going to be the most particular agent

35:40that has been shown to cause it actually

35:42can lead to reversible uh visual

35:44dysfunction but so if your patient has

35:45this kind of like visual dysfunction

35:47when they take for a console you can

35:48just either decrease the dose or

35:50remove the medication if they can't

35:51tolerate it and then they'll have you

35:53know complete gain of function back of

35:54their eyes again

35:56but these are the medication adverse

35:57effects that i want you guys to watch

35:58out for with the azoles the gricio

36:00fulvin is the other one and this is why

36:01we kind of switch to terbenaphine

36:03generally

36:04um in comparison to graciofulvin for

36:06like oncomycosis and a lot of the

36:08dermatophyte infections you use other

36:09agents like your azoles or your your

36:12topical asos or your oral asylums

36:14graciofulvin is pretty hepatotoxic

36:16that's one thing so you definitely

36:17because of that

36:18you want to monitor the patient's lfts

36:20and to be honest with you it's probably

36:21not a bad idea if a patient asks you

36:22know if you're asking the question what

36:23kind of labs would you want to monitor

36:25in a patient taking antifungals i'm sure

36:27the lfts you probably won't go wrong to

36:28be honest with you the other thing is

36:30azol's our cyp450 inhibitors

36:33this bad boy is a

36:35cyp-450 inducer

36:38so meaning it actually is going to

36:40decrease the concentration of the actual

36:42drug circulating so if a patient is

36:43taking warfarin

36:45and you give them

36:47um a gracial folate then gristiofolive

36:49will act as an inducer reduce the

36:51concentration of the warfarin making

36:52them less able to

36:54well actually in this situation if you

36:56decrease the concentration of warfare

36:57now they're getting actually clot so

36:58that's the problem with that one so

37:00think about that with other drugs that

37:01they may be taking and maybe reducing

37:02the efficacy of those particular drugs

37:05the next thing is teratogenic and

37:06carcinogenic so do not give this to

37:08people who are actually pregnant so

37:10that's one particular thing to remember

37:11and also if you really want to add this

37:13one in you have the brain space is it

37:15also has been shown to cause a

37:16disulfiram reaction so it can cause that

37:18kind of nausea vomiting flushing maybe

37:20even hypotension when you take this with

37:21alcohol

37:22the last particular drug here is

37:24flucytosin so just like gristio fulvin

37:25is toroidogenic flucytosine is also

37:28teratogenic so don't give this to

37:29patients who are pregnant and the last

37:30thing is it can actually suppress the

37:32bone marrow and prevent the production

37:33of all cell lines so it can drop the

37:36production of your white blood cells

37:39and it can drop the production of your

37:41red blood cells

37:43and it can drop the production of your

37:44platelets so what do we call that

37:45whenever actually you drop all the

37:47actual cell lines both the white blood

37:49cells the white uh the platelets and on

37:52top of that

37:53the red blood cells this is called

37:55pancytopenia

37:56so watch out for pancetta penis or

37:58monitor their cbc whenever you have a

38:00patient who is on

38:03flu cytosine

38:04all right my friends i know you think

38:05that that's it but we're not done we got

38:07to review this stuff because there was a

38:08lot that we covered so let's actually do

38:09some cases see if you guys can remember

38:11all this stuff and let's get at it

38:12what's up ninja nerds all right so let's

38:14go ahead and do some cases here we got

38:16to talk about some antifungals all right

38:18so your infectious disease attending is

38:20performing his rounds and he decides to

38:22say okay i'm going to ask you some

38:23questions about antifungal therapy and

38:25let's go through their mechanism of

38:27action so he's going to pimp you out a

38:29little bit quizzy he says okay which

38:30drugs inhibit the squalene oxidase

38:33reducing the formation of linosterol in

38:35our gastro thereby reducing the

38:37stability of the cell membrane do you

38:38guys remember this you have squalene

38:40esquilion epoxide to linosterol to our

38:42gastro which is important incorporating

38:44into this cell membrane stability so if

38:47i give a drug to inhibit this create

38:49squalene oxidase this would be

38:50terbenifene the next one would be which

38:53is the drug that inhibits this cute

38:54little enzymes let's go to that one

38:56which is the one that inhibits the

38:57cytochrome p450 14 alpha dimethylase

39:00enzyme this is going to be which one do

39:03you guys know the azoles so this is your

39:05triazoles voriconazole itraconazole

39:08isobuconnazole posaconazole fluconazole

39:10and then your imidazoles which is

39:12mechanozole chloramizal and

39:14ketoconazole good again both of these

39:17are inhibiting the formation of

39:18ergosterol which is important in cell

39:21membrane stability so terbenifene and

39:24azol's inhibit ergosterol formation

39:27all right which ones actually bind with

39:29ergosterol kind of form a pore because

39:32it has a hydrophilic and a hydrophobic

39:34portion

39:35and when it binds to this our gastro

39:37creates a little pore that allows for

39:38ions to move in and out which can create

39:40the opportunity for cell lysis

39:42this is

39:44which ones do you guys remember which is

39:45the ones that actually form the pores

39:48these are the ones like nestatin and

39:50amphotericin b

39:52all right beautiful all right so the

39:54next thing is we're going to move on to

39:56the drugs that inhibit the beta 1 3

39:58glucan

39:59synthase this is the guy that makes the

40:01beta 1 3 glucans which are important in

40:02cell wall stability resistance to

40:04osmotic forces

40:06if we inhibit this particular enzyme

40:08that will actually reduce the formation

40:09of these cell wall structures and reduce

40:11the ability to resist osmotic forces

40:13causing cell death this will be

40:15the kind of cannons microfungan caspar

40:18fungi right beautiful

40:21all right which is the ones that

40:22actually binds to the microtubules

40:24particularly the tubulin proteins

40:25inhibits the microtubule so now that you

40:27can't actually separate the chromosomal

40:29dna and help with the actual division of

40:32fungi passing on genetic material this

40:35is

40:36griseo fulvin beautiful i know you guys

40:39are killing it all right which is the

40:40one that actually comes into the cell

40:42gets converted into five floor uracil vi

40:44cytosine deaminase binds with the actual

40:47dna inhibits it from being able to

40:48undergo dna replication and also dna

40:51transcription

40:53this is

40:54flue cytosine beautiful all right we

40:56move on now into the first case he says

40:59okay you have a patient has

41:00oropharyngeal candidiasis they got some

41:02thrush there what's the treatment what

41:04are the actual opportunities of what

41:06kind of drugs would you use you can say

41:08oh you can use the nostatin you can

41:09swish and swallow or the clutch

41:11tramazole lozenges

41:12beautiful done

41:14all right he says okay you actually have

41:16a patient who has esophageal candidiasis

41:19and you see this here look at all that

41:21oh man that's rough what are you going

41:23to do for this patient this is oral

41:24fluconazole or itraconazole beautiful

41:28all right you have a patient has volvo

41:29vaginal candidiasis what are the

41:31treatment options for this one well

41:33first one we can consider is

41:35the topical azole's the imidazole so

41:38type of topical meconazole topical

41:41clatrimozole and if that doesn't work po

41:43fluconazole and if that doesn't work flu

41:45cytosine you guys remember this right

41:48all right beautiful

41:50all right patient has intertriginous

41:52candidiasis meaning that they have some

41:53candida in the actual different folds

41:56like underneath the breast in the axilla

41:57and the anal anogenital area what would

42:01a potential treatment for this be we

42:03could do the statin topical beautiful

42:06all right we have a patient who has

42:07systemic or invasive candidiasis that's

42:10invaded their blood so there's in their

42:12systemic circulation it's caused

42:13endocarditis it's caused a urogenital

42:16tract infection it's caused an ocular

42:18infection some type of nasty invasive

42:20candidiasis what are the particular

42:22treatment options for these patients you

42:24can do which one

42:26the echino candidates are going to be

42:28really good at this but you can also

42:29consider like pio fluconazole as well

42:32right and last but not least

42:33amphotericin

42:35all right you have a patient who has

42:37invasive aspergillus so aspergillus is a

42:40nasty thing that can cause like allergic

42:42bronchopulmonary aspergillus then it can

42:44actually cause like a pneumonia like a

42:45nodular kind of pneumonia it can cause

42:48aspergillomas like these fungal balls

42:50that can actually appear and it can

42:51really cause cavitations and can even

42:53spread throughout the body what will be

42:55the particular treatment options for

42:56this what's the always the first line

42:58voriconazole yep then

43:00isoviconazole echinocandins and

43:03amphotericin b is another option

43:06all right patient has a cryptococcal

43:08meningitis and pneumonia what are the

43:10particular

43:11treatment options so you treat this

43:12within the first two weeks

43:14induce them with

43:15flu cytosine and

43:18what else amphotericin b and then after

43:21that we can put them on fluconazole for

43:23after that two weeks is maintenance

43:24therapy you guys remember that all right

43:27cool we have a patient who has what's

43:29called either blastomycosis or

43:31histoplasmosis or

43:33coccidiomycosis and as we talked about

43:34this is kind of an endemic endemic type

43:37of fungal infection that's dependent

43:38upon the geographical location that

43:40you're at so as you can see

43:42histoplasmosis would be in this part of

43:44the actual u.s and you can see

43:46blastomycosis in this part of the u.s

43:49and then again you can see

43:50coccidiomycosis over here in this

43:52particular part of the u.s so it's

43:54obviously dependent upon the geographic

43:55location but either way it can cause you

43:58know pneumonia meningitis skin bone

44:00infections

44:01so because of that what are the

44:02particular treatment options for blasto

44:04histo or coccidio what is it

44:07itricondazole's first line fluconazole

44:10is another option and then if you can

44:12actually consider adding on amphotericin

44:14b to fluconazole especially in those

44:16severe refractory cases

44:18all right patient has rhinos cerebral

44:20and lung mucour mycosis really nasty

44:22type of infection if they have this

44:25people who are at high risk for this is

44:26patients who are diabetic or hiv

44:29positive in this situation what's the

44:31preferred treatment for mucor it would

44:33be isobuconazole at its first line other

44:36ones would be amphotericism b if they're

44:38contraindicated of taking isoviconazole

44:40and then you need to consider

44:42debridement of the actual infected area

44:45our patient has teenia versacolor if

44:47they have teenia versicolor right this

44:49type of dermatophyte infection what do

44:51you treat these patients with

44:52topical ketoconazole would be the

44:55preferred one or mica micondazole all

44:57right you have a patient who has a

44:59terrible day they have tinea capitis

45:01teneocriporus tina cruz and tediopetis

45:05right so they have an infection of this

45:07actual nasty uh fungus on the head they

45:11have it on the body they have it at the

45:12growing

45:13okay and even out of the feet if this

45:15happens what is the particular treatment

45:18for these patients

45:19in a theoretical world we would treat

45:21them with topical agents first

45:23myconazole chloramizal ketoconazole we

45:25could even escalate to po itraconazole

45:29and then if that doesn't work we can

45:30even consider something like

45:32griseofulvin

45:33now if a patient has teenia ungium or

45:36what's called

45:37anecomycosis this is a really nasty

45:39infection that will not respond to

45:41topicals and really the only thing is

45:44piotr benefiting and some even say

45:46griseofolvin but turbinifen would be the

45:48preferred option

45:49all right engineers we covered all of

45:51the cases that i want you guys to

45:52remember for your anti-fungals i hope

45:55this made sense i hope that you guys

45:56enjoyed it as always love you thank you

45:59and until next time

46:04[Music]

46:20you