[HN Gopher] New antifungal therapy for fungal meningitis
___________________________________________________________________
New antifungal therapy for fungal meningitis
Author : gmays
Score : 167 points
Date : 2023-08-31 13:24 UTC (9 hours ago)
(HTM) web link (med.umn.edu)
(TXT) w3m dump (med.umn.edu)
| DoreenMichele wrote:
| _Conventional amphotericin B can only be administered directly
| into veins and is highly toxic. The new lipid nanocrystal
| formulation...can be taken orally and is non-toxic.
|
| "An orally administered amphotericin that is effective against
| nearly all fungus and non-toxic sounds like the holy grail of
| antifungal medicines..._
|
| This is good news, though you can bet money that fungal
| infections will eventually adapt. They need to stop acting like
| _we have solved it once and for all_! It 's an ongoing battle and
| as we change tactics, the invaders into our bodies change tactics
| too.
| cyberax wrote:
| Amphotericin and its derivatives work by binding with
| ergosterol, creating pores in the fungal cell membrane.
| Ergosterol is a small molecule, not a protein, so it can't be
| easily mutated. It also is a part of the membrane, so it's
| always exposed.
|
| All observed resistance mechanisms (so far) work via active
| counter-measures, such as additional ion pumps, and they reduce
| the fitness of fungal cells as a result.
| DoreenMichele wrote:
| _All observed resistance mechanisms (so far) work via active
| counter-measures, such as additional ion pumps, and they
| reduce the fitness of fungal cells as a result._
|
| No, if it allows the organism to survive, it increases
| fitness by definition. "Survival of the fittest" does not
| mean "All those fungal cells who went to the gym and ate
| right and look like Arnold Schwarzenegger get to live because
| they are so beautiful." It often means the equivalent of drug
| addicts on skid row, so long as they live longer with the
| "bad" choice than without it.
|
| Sickle Cell Anemia reduces fitness compared to people without
| the disorder -- unless you live someplace with malaria and no
| effective treatment for it, in which case you live longer if
| you have Sickle Cell Trait than if you don't and, gee, too
| bad, so sad that having two copies of the gene is so
| torturous and debilitating.
|
| Survival of the fittest is a war of attrition. It's _last man
| standing_ no matter how awful he looks or terrible he feels.
|
| It's not _we can build a better organism if we plan this in
| advance, one that is stronger and faster and prettier._
| r2_pilot wrote:
| Interestingly, resistance to amphotericin has generally been
| pretty limited as adapting to it is heavily adverse to the
| fungus living in the body, which then allows (generally) the
| body to clear it out after it's made its suboptimal
| adaptations.
| Traubenfuchs wrote:
| Stable resistance
| exists:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC105185/
| amluto wrote:
| That's describing something interesting, but it doesn't
| sound like stable resistance. It's a short lived resistance
| induced by exposure to other drugs.
| Traubenfuchs wrote:
| ...there are studies from pre 2000 showing resistance
| development. So: Yes.
| [deleted]
| azan_ wrote:
| > Cryptococcal meningitis is the most common cause of central
| nervous system infection in people living with HIV worldwide.
| Isn't HIV encephalitis more common?
| DoreenMichele wrote:
| Encephalitis is inflammation of the brain. It can be _caused_
| by infection but the word does not actually describe infection
| per se.
| haldujai wrote:
| I think the commenter is referring to acquired HIV
| encephalitis caused by direct HIV infection which I was also
| under the impression was the #1 CNS infection in HIV
| patients.
|
| My teaching (in radiology) was HIV > toxoplasmosis >
| cryptococcosis for CNS infections in HIV+ but maybe we're out
| of date or this order is sepcific to the US/Canadian
| population.
|
| Anecdotally I've definitely seen more toxo than crypto. I've
| also seen more white matter disease in HIV patients than
| either but the MRI findings aren't specific so I don't know
| what the final path was on those cases.
| obloid wrote:
| In our HIV patients we see more more cryptococcal
| meningitis than CNS toxoplasmosis. Crypto is typically not
| going to have any significant radiologic abnormality unlike
| toxo in which imaging plays a large role in diagnosis. So
| I'm guessing, being a radiologist, you've got a sampling
| bias that favors toxo.
|
| PO amphotericin B would be a huge boon in treating these
| patients and shortening hospital stays. Outpatient Ampho B
| is not a good option in most cases.
| haldujai wrote:
| Just in case it's not clear I am by no means claiming
| domain expertise, merely stating that what I was taught
| and my understanding was similar to the initial comment I
| replied to hence the caveats and soft language. My
| statement should not be read as contradicting an ID
| expert or claiming that the author of the article is
| incorrect.
|
| > In our HIV patients we see more more cryptococcal
| meningitis than CNS toxoplasmosis. Crypto is typically
| not going to have any significant radiologic abnormality
| unlike toxo in which imaging plays a large role in
| diagnosis. So I'm guessing, being a radiologist, you've
| got a sampling bias that favors toxo.
|
| Agree crypto is much more subtle on imaging than either
| HIV encephalitis or toxo, the most common finding we see
| is dilated PVS which is nonspecific (particularly without
| priors). I only mentioned my anecdotal experience as it
| corresponds with what's taught to us but I agree it's
| highly susceptible to bias and I don't consider it
| evidence.
|
| For example on StatDx (UpToDate for radiologists):
|
| > _[Cryptococcus is the] most common fungal infection in
| AIDS patients_
|
| > _3rd most common [CNS] infection seen in AIDS patients
| (HIV > toxoplasmosis > Cryptococcus)_
|
| This could very well be out of date/incorrect, they don't
| give in-text citations like UpToDate so I'm not sure
| where these specific statements are coming from.
|
| Do you have a reference handy? If so I can submit it as
| feedback on the article to get it updated/reviewed.
| obloid wrote:
| Honestly there is conflicting information about which is
| more prevalent (toxo or crypto). From what I've found the
| sources that site toxoplasmosis as most common are older,
| and the ones reporting cryptococcal meningitis as more
| common are more recent. I suppose the incidence may have
| shifted since the 90s. I don't really know. Anecdotally I
| see more crypto (private practice ID in southeast US).
| haldujai wrote:
| Interesting. Probably did shift then, it would fit the
| pattern of epidemiological changes taking a while to
| percolate to radiology and as it's far more likely we
| miss crypto on MRI than toxo we probably wouldn't notice
| a change in our reporting incidence to make a radiologist
| question that ranking.
|
| Thanks for taking the time to search and comment. Always
| appreciate learning from my clinical colleagues + now I
| can flex a new obscure fact to radiology trainees like a
| proper academic physician.
| 1letterunixname wrote:
| This is good news given risks of systemic side-effects when
| infused, including cytokine storm and multiple organ failure
| incl. hepatoxicity.
|
| There is a critical shortage of classes of antimycotics. For
| example, 3 medications of the echinocandin class remain useful in
| treating multi-drug resistant c. auris, the beastie that
| sometimes requires throwing out durable hospital equipment and
| tearing out the walls due to contamination.
|
| https://slate.com/technology/2019/04/candida-auris-hospitals...
| krylon wrote:
| There is _fungal_ meningitis, too? You really do learn something
| new every day. That does sound very bad, but meningitis always
| is.
| Zelphyr wrote:
| My father contracted cryptococcal meningitis seven years ago and,
| according to his doctors, was days away from dying from it (he
| has fully recovered since, thankfully)
|
| The problem, though, wasn't treating it. His neurosurgeon told me
| they treated it with the same medication they give women for
| yeast infections. The problem was diagnosing it. He's not HIV
| positive nor has he had a transplant. Apparently, in a small
| percentage of the population, the fungus makes it way to a non-
| immunocompromised brain. It's so small that, according to his
| neurosurgeon, they have to treat patients like him as if they
| were HIV positive/transplant recipients because they don't have
| enough data otherwise.
|
| I'm glad to hear about this new therapy but, with my father at
| least, they weren't able to properly diagnose until they did a
| biopsy on his brain. So, it seems like improvements in diagnosis
| may be in order as well.
| darkclouds wrote:
| > the fungus makes it way to a non-immunocompromised brain.
|
| Something I'm looking at the moment is the role zinc plays in
| things like membranes and blood brain barrier.
|
| When looking at how much zinc is used through out the body
| which combined with one of these, cysteine, histidine, aspartic
| acid, glutamic acid, with the first two largely involved in
| structural applications ranging from zinc fingers to organelle
| stability, cell stability and membrane health, it looks like
| the RDA is woefully inadequate.
|
| The problem is a blood test wont show zinc status as its so
| tightly controlled in serum, so if its measured and it shows a
| problem, its going to be an extreme problem. However if you
| suffer a head injury, the damaged brain cells will dump zinc
| straight away into the blood so that the neurons take up
| glutamate which then become neuro toxic leading to cell death.
|
| For example, if you take vitamin D3 supps, it needs a zinc
| finger, so taking VitD3 with zinc, is useful other wise you
| could be wasting your time taking VitD3 if there is simply not
| enough zinc in the body, which can explain why some people dont
| respond to vit D3 supps.
|
| If the zinc status is low, there are so many vitamins and
| minerals that are just not worth doing.
|
| But mega dosing so many vitamins and minerals can create a zinc
| deficiency, like mega dosing vit A or D, or even nicotinic acid
| (b3) to compound things.
|
| Its not been unheard of taking a few hundred mg's a day, with
| documented therapeutic doses at 2grams a day! There is also
| disputes over whether an increased zinc intake even causes
| copper deficiency's. Studies are mixed, so typical medical
| caution is order of the day with regard to high doses of zinc,
| but that caution can contribute to medical conditions.
|
| The digestive system has no restriction on the uptake of zinc,
| unlike iron which uses hepcidin, but things like fibre,
| phytates, tannins, found in vegetables, will all bind to zinc
| in the gut very easily reducing its effectiveness, and then
| there is calcium, iron which is known to compete, with
| phosphate also looking like a similar competitor of zinc.
|
| B6 is recommended for any high intakes of minerals, it can be
| used to reduce the incidence of sideroblastic anemia and
| peripheral neuropathy amongst many things.
|
| The Nicotinic Acid form of B3 works with every enzyme in the
| body via Nicotinamide Adenine Dinucleotide (NAD) and Adenosine
| triphosphate (ATP).
|
| But as there is no reliable way to measure zinc status, things
| like an enlarged spleen (splenomegaly), cancer, diabetes, and
| numerous more disease states and illness could indicate an
| inadequate zinc status. Put another way, Zinc deficiency is
| found in so many illnesses including depression.
|
| > > weren't able to properly diagnose until they did a biopsy
| on his brain.
|
| Did they measure the surrounding tissue around the brain and
| bone mineral density, to check if the blood brain barrier was
| intact, and immune response optimal?
|
| If its any consolation, fungi can be sniffed as a smell and end
| up in the sinuses where they can contribute to mental health
| issues, but these only show up in autopsy's, and biopsy's!
|
| When zinc acetate at 75mg was used to shorten the common cold,
| its typically portrayed that it shortened the cold duration by
| a couple of days and its not really worth taking.
|
| When looking at the studies, the common cold had a typical
| 8.3day duration but with a total 75mg of zinc acetate spread
| over a day, reduced it to a 4.5day duration. Take into account
| the time it takes for the immune cells to respond, with or with
| out supplement, and that zinc duration could be reduced to
| under 4 days, even fewer days if there was adequate zinc status
| before infection, making it much more significant and effective
| than its currently portrayed!
|
| So, should we be re evaluating our zinc intake to see
| improvements in health, to avoid situations like this?
| Zelphyr wrote:
| Interesting. I take a vitamin D3 supplement daily because a
| physical a couple of years ago showed I was a little low (I
| do keto so I'm assuming that's why). Sounds like I may need
| to add a Zinc supplement as well?
|
| > Did they measure the surrounding tissue around the brain
| and bone mineral density, to check if the blood brain barrier
| was intact, and immune response optimal?
|
| Not that they ever mentioned to me.
|
| > If its any consolation, fungi can be sniffed as a smell and
| end up in the sinuses where they can contribute to mental
| health issues
|
| The best theory we can come up with is that he contracted the
| fungus while crawling under a house.
| andai wrote:
| How are brain infections of other types normally diagnosed?
| haldujai wrote:
| It depends on what type of infection we are worried about and
| what structures are involved but generally an MRI and a
| lumbar puncture for cerebrospinal fluid analysis to start. If
| there's an abscess a neurosurgeon can stick a needle/drain in
| it.
|
| Usually a combination of clinical and MRI findings is enough
| for infectious diseases and neurology specialists to figure
| it out and start empiric treatment for something/a few
| somethings if the CSF doesn't give you the answer.
|
| Rarely, at least at my institution, you could do a biopsy but
| you don't really want to be chopping up the brain if you can
| avoid it.
| onemoresoop wrote:
| And are there any particular worrying symptoms for this type
| of brain fungal infections?
| Zelphyr wrote:
| I can't speak to what's common but, with my dad it was he
| was increasingly confused, constantly tired and sleeping
| all the time, and progressive weight loss. He was down to
| 100lbs when they admitted him.
| pmags wrote:
| Treatment is in fact a real challenge. Cryptococcus isolates
| "in the wild" have a relatively high frequency of azole
| resistance alleles already (azoles are what you give someone
| for a typical "yeast" infection), and azole resistances arises
| relatively quickly in patients in both patients and animal
| models of disease. Coupled with this is the fact that fungi are
| eukaryotes, and hence share most of their core cell and
| molecular biology with your own cells. Hence treatments that
| specifically target the fungal cell with little toxicity to
| your own cells are hard to come by.
|
| Note that last year the WHO released a list of "fungal priority
| pathogens" based on criteria related to "unmet research and
| development needs and perceived public health importance."
| Cryptococcus is at the top of this list.
|
| https://www.who.int/publications/i/item/9789240060241
|
| General resources on fungal meningitis:
|
| https://www.cdc.gov/meningitis/fungal.html
|
| CDC resources specific to Cryptococcus:
|
| https://www.cdc.gov/fungal/diseases/cryptococcosis-neoforman...
| gambiting wrote:
| A lot of virus infections are unfortunately like that too. Few
| years ago I had a fever that wouldn't go away, night sweats, no
| appetite, nothing......finally got admitted to a hospital with
| an infectious diseases department, they ran about 40 different
| tests.....all negative. Did few dozen more, this time on all
| kinds of tropical/exotic diseases.....all negative. Few weeks
| of back and forth while I was still _very_ unwell, losing a lot
| of weight. The doctor looking after me was suspicious it 's
| actually HIV that's not coming up on the tests for some reason,
| repeated the tests like 3 times just to be super extra
| sure.....eventually they just said "it's some kind of virus but
| we don't know what, so we have no idea - go home and rest, it
| should improve within few weeks but in the meantime we have no
| solution for you".
|
| Couple weeks later several of my joints got really swollen
| which led to them testing me for a human Parvovirus-B6
| infection, and indeed, that's what it was - but it was just a
| lucky guess by the doctor there, he said they don't normally
| test people in my age group for it because it's incredibly rare
| for adults to get infected or show any symptoms, but lucky me,
| I was in that 0.000001% group that not only got infected by
| also had severe symptoms. But even then it was just "ok, we
| know what it is but there is nothing we can do to help, it
| should go away, oh and btw there is a 5% chance you will
| continue getting symptoms for years if not forever". Well it's
| been 4 years and I'm still fighting it, so...........
| 1letterunixname wrote:
| I can't find any reference to "Parvovirus-B6" in the
| literature or any taxonomy. There is only Parvovirus-B19, the
| near ubiquitous causative agent of the childhood infection
| known as fifth's disease. Are you immunocompromised? Has any
| radical treatment such as convalescent plasma been
| considered?
|
| https://virologyj.biomedcentral.com/articles/10.1186/s12985-.
| ..
|
| Note that the attached figure describes pathogenicity as
| affecting any animal host, not just humans.
| gambiting wrote:
| Yes, B19, sorry don't know why I said B6.
|
| And yes it's very common in children with mild symptoms,
| and in adults it's extremely rare to have any symptoms at
| all(from what I understand it's actually not well studied
| how common it is as an infection because the symptoms
| either don't exist or are the same as normal cold so no one
| gets tested for it). At the hospital at the specialized
| infectious diseases unit they told me they have only seen 5
| adults with it in the last 10 years and I've been the worst
| case they had.
|
| >>Are you immunocompromised?
|
| No
|
| >>Has any radical treatment such as convalescent plasma
| been considered?
|
| Not that I know. I did eventually start recovering so I
| guess they didn't want to go nuclear.
| 1letterunixname wrote:
| No worries.
|
| I hope they publish a case study article as a clinical
| treatment guide for the next cases.
|
| Your kind of situation exposes one of the current
| inadequacies of the clinical medical profession: falling
| through the epidemiological cracks of rare diseases and
| syndromes. There is a finite amount of evidence-based
| medical knowledge and an inability to rapidly test and
| adapt to infinite presentations that don't fit neatly
| into an "average" common case. Perhaps we need both
| cheaper lab tests/diagnostic procedures (not Theranos in
| execution but close to it) and tens of thousands more
| "detective" MD researchers meeting up with clinical side
| of the healthcare industry to elucidate the unknowns and
| the unexplained rather than shrug of patient concerns
| lacking clear explanations. Lastly, clinical MDs should
| aim to never forget their roots by publishing more.
| TheSpiceIsLife wrote:
| May I ask some questions:
|
| Your white cell counts were indicative of viral infection?
|
| PCR was positive, indicating infection?
|
| Do you supplement zinc, C, B6, magnesium?
| gambiting wrote:
| For 1 and 2 I don't know, I assume so, they never showed me
| any stats at the hospital.
|
| And yes I do, all of those + vitamin D.
| _a_a_a_ wrote:
| May I ask why you'd want to know about zinc, C, B6,
| magnesium specifically?
| 1letterunixname wrote:
| Be careful with supplementation of transition metal trace
| elements. Absorption of one is usually competitive to
| others such that it cause toxicity in one and deficiency in
| another. A multivitamin is a safer source but having blood
| levels checked regularly would allow for calibrated intake.
|
| For example, as a poor absorber of Vitamin D3 I require 12k
| IU / day (with all of its cofactors) to stay within the
| established blood range. It would be inadvisable and
| reckless for anyone to consume this amount of a fat soluble
| vitamin without monitoring blood levels. I'm also prone to
| iron deficiency anemia of unknown etiology (cause), but
| that's another problem suggesting either poor absorption
| (most likely), cancer, or unexplained bleeding.
| stef25 wrote:
| So the fungus can cross the blood brain barrier? Or does it get
| there via other means?
| haldujai wrote:
| Yes. Microbes once in the blood stream can cross/bypass the
| barrier by a few ways such as by crossing endothelial cells,
| crossing loosened or disrupted tight junctions or by entering
| a host cell that then traverses the barrier.
|
| Normally, intact cell-mediated immunity prevents harmless
| airway colonization of these types of organisms from entering
| the blood stream or causing clinical infection hence why
| they're called opportunistic infections. Rare in
| immunocompetent patients.
| Zelphyr wrote:
| The surgeons never said one way or another. I got the
| distinct impression that they are, unfortunately, at quite a
| loss when it comes to people like my dad since he shouldn't
| have been immunocompromised. In fact, prior to the biopsy,
| they were convinced it was some form of cancer.
| epistasis wrote:
| Thanks for sharing this. The diagnostics world is advancing
| quickly due to our exponential tech curve on DNA sequencing,
| but that's not going to solve the problem of needing a brain
| biopsy to diagnose...
|
| Do you know if they did testing of easier material like
| cerebral spinal fluid first?
| Zelphyr wrote:
| They did but couldn't detect the fungus from that so they
| proceeded to the biopsy. The surgeon said that the cerebral
| spinal fluid can get filtered quite a bit by the time it gets
| to the area where they do the tap which was why they couldn't
| detect it using that method.
| jonplackett wrote:
| Does this mean we can finally stop worrying about The Last of Us
| ever coming true?!?!
| treprinum wrote:
| How does apolactoferrin fare in comparison to amphotericin B?
___________________________________________________________________
(page generated 2023-08-31 23:00 UTC)