I was contacted by a reader in Italy whose child with autism may respond to bumetanide, but has a sulfonamide allergy and got a skin reaction (hives). She had to stop giving the drug, but wanted to know how she could re-start bumetanide.
Other readers have pointed out
how they dare not try bumetanide because they know their child has a
sulfonamide allergy. I think our longtime reader Tanya is one example.
Key
Point to Note
Most people discover their
sulfonamide after being giving an antibiotic in early childhood.
It is now well established that
many (but not all) people with an allergy to sulfonamide antibiotics can safely
take a sulfonamide diuretic like Bumetanide or Diamox/Acetazolamide. This is presented
in case studies later in this post.
Sulfonamide
Drugs
Many common drugs are
“sulfonamides”. Their chemical structure includes a sulfonyl (–SO2)
group attached to an amine group (–NH2). They include common antibiotics, like erythromycin,
many diuretics (bumetanide, furosemide, acetazolamide (Diamox), some
anticonvulsants (zonisamide) and some anti-inflammatory drugs (sulfasalazine).
Sulfonamide
Allergy
Many parents discover early in their
child’s life that their child has a sulfonamide allergy. Sometimes this is abbreviated
to a “sulfa allergy.”
The symptoms of a
sulfonamide allergy can vary but may include:
- Skin reactions (rash,
hives, or itching)
- Fever
- Swelling
- Respiratory issues (shortness
of breath)
- Anaphylaxis (in severe
cases)
Usually the symptoms are minor, but once
diagnosed the parents usually take note never to give their child any
sulfonamide drug.
If you have the
allergy must you avoid all sulfonamide drugs?
The standard assumption has been that
if you have a sulfonamide allergy you cannot take Bumetanide or Acetazolamide
(Diamox).
Upon further investigation in the
research, this may not always be true.
What happens when
there is no alternative drug?
When treating ion channel/transporter
dysfunctions there may not be a non-sulfonamide alternative.
Acetazolamide (Diamox) is
documented in the literature as a case in point. Bumetanide has not yet made it
to the literature.
Furosemide fortunately has been
researched and a safe desensitization protocol exists. Furosemide is a very
similar drug to bumetanide.
Desensitization strategies
I did recently write about enzyme potentiated
desensitization, which is an old, mostly overlooked, technique to overcome
allergic reactions. I was interested in pollen allergy.
The best-known kinds of desensitization are allergy shots and more recently overcoming nut allergies, which gets media attention.
Oral
immunotherapy for peanut allergy in young children
The study also found that the youngest children and those who started the trial with lower levels of peanut-specific antibodies were most likely to achieve remission.
“The
landmark results of the trial suggest a window of opportunity in early
childhood to induce remission of peanut allergy through oral immunotherapy,”
says NIAID Director Dr. Anthony Fauci. “It is our hope that these study
findings will inform the development of treatment modalities that reduce the
burden of peanut allergy in children.”
I did wonder that if it works for nuts
then why not bumetanide.
It turns out that I am not the first
to consider desensitization to a drug allergy. The best known method is rapid drug
desensitization (RDD), usually intravenous, which opens a window to be able to start
taking a drug you are allergic to. Once you stop taking the drug, you then
again become allergic to it.
The other
approach is more like dealing with nut allergies, it is called slow drug
desensitization (SDD) and involves taking a tiny initial dose and then slowly
increasing it over weeks and months.
Drug desensitization
is normally done in hospital as part of some therapy when you absolutely must
have a drug that you are allergic to.
The paper below
contains information on a very large number of common drugs where drug desensitization
has been successfully carried out.
Desensitization for the prevention of drug hypersensitivity
reactions
Drug desensitization is the temporary induction of tolerance to a sensitized drug by administering slow increments of the drug, starting from a very small amount to a full therapeutic dose. It can be used as a therapeutic strategy for patients with drug hypersensitivity when no comparable alternatives are available. Desensitization has been recommended for immunoglobulin E (IgE)-mediated immediate hypersensitivity; however, its indications have recently been expanded to include non-IgE-mediated, non-immunological, or delayed T cell-mediated reactions. Currently, the mechanism of desensitization is not fully understood. However, the attenuation of various intracellular signals in target cells is an area of active research, such as high-affinity IgE receptor (FcɛRI) internalization, anti-drug IgG4 blocking antibody, altered signaling pathways in mast cells and basophils, and reduced Ca2+ influx. Agents commonly requiring desensitization include antineoplastic agents, antibiotics, antituberculous agents, and aspirin/nonsteroidal anti-inflammatory drugs. Various desensitization protocols (rapid or slow, multi-bag or one-bag, with different target doses) have been proposed for each drug. An appropriate protocol should be selected with the appropriate concentration, dosage, dosing interval, and route of administration. In addition, the protocol should be adjusted with consideration of the severity of the initial reaction, the characteristics of the drug itself, as well as the frequency, pattern, and degree of breakthrough reactions.
Two categories of desensitization protocols are currently available: RDD and slow drug desensitization (SDD). RDD is recommended for immediate reactions, both allergic and nonallergic. The most widely used RDD protocol is doubling the dosage every 15 minutes until the therapeutic dose is achieved. SDD is recommended for type IV delayed hypersensitivity reactions with T cell involvement, and can be performed both orally and intravenously. There is as yet no consensus on SDD protocols, including the initial dose, dose increments between steps, and dosing interval. Further clinical experience and research are required to establish the role and efficacy of desensitization for delayed reactions.
H1 blockers, H2 blockers, and glucocorticoids can be used as premedication. Aspirin and montelukast block the end products of the arachidonic acid cascade and decrease the incidence and severity of BTRs. NSAIDs can help to control the symptoms of cytokine release syndrome. Glucocorticoids alone are not recommended because they cannot prevent the initial degranulation of mast cells.
The desensitization process is known to be antigen-specific,
as the level of drug-specific immunoglobulin E (IgE) decreases but the levels
of other allergen-specific IgE remain consistent throughout the treatment
period. However, the cellular and molecular mechanisms underlying drug
desensitization are not yet fully understood.
Aspirin/NSAID desensitization is considered for patients with
cardiovascular or musculoskeletal diseases who require aspirin or NSAID
administration for prolonged periods.
The temporary
tolerance to aspirin/NSAIDs lasts 48 to 72 hours after desensitization.
Therefore, hypersensitivity reactions can recur 2 to 5 days after
discontinuation if the therapeutic dose is not continued.
DHR to β-lactams, such as penicillin or cephalosporin, is
more common than that to non-β-lactams. Desensitization can be performed for
both immediate and delayed hypersensitivity reactions. The protocol should be
selected based on patient characteristics, hospital capacity, and physician
preferences. It is generally started with 1/1,000 of the therapeutic dose and
then increased by 2 to 3-fold every 15 minutes to 5 hours. Oral administration
is preferred due to its ease, safety, and effectiveness. Desensitization to
penicillin and cephalosporins has been well established. Successful desensitization has
also been reported for other β-lactams, such as carbapenem and monobactam, and
non-β-lactams, such as vancomycin, clindamycin, metronidazole, macrolides,
aminoglycosides, tetracycline, and ciprofloxacin.
Successful
desensitization to other antimicrobials has also been reported for antifungals, such as amphotericin B,
fluconazole, itraconazole, voriconazole, and micafungin, and for antivirals,
such as acyclovir, valganciclovir, ribavirin, and nevirapine.
Furosemide desensitization
There is no literature specific to bumetanide but there
is on the very similar drug furosemide.
RAPID ORAL DESENSITIZATION TO FUROSEMIDE
Furosemide is a commonly used loop diuretic that contains a
sulfonamide group. Although there are rare reports of hypersensitivity to
furosemide, severe reactions, including anaphylaxis, have been reported.
Ethacrynic acid, the only loop diuretic without a sulfonamide moiety, is no
longer available in oral formulation, thus posing a dilemma in the outpatient
treatment of patients with furosemide allergy.
Published protocols for furosemide desensitization include
rapid intravenous administration and oral protocols lasting 3 to 10 days.3–5
The oral protocols were performed in patients with non–type I hypersensitivity
reactions. We present a rapid, oral protocol for desensitization in a patient
with presumed type 1 furosemide allergy manifesting as urticaria.
Desensitization to sulfonamide-containing antibiotics has
been extensively used, but desensitization to furosemide is uncommon. The oral
protocols previously described took 3 to 10 days and were performed in patients
with non–type I hypersensitivity reactions, one with pancytopenia and the other
with pancreatitis. The patient with a type I hypersensitivity reaction
underwent an intravenous desensitization protocol. Rapid oral desensitization to a loop diuretic has
not been previously described. The potential advantages of oral desensitization
are that it is probably safer than intravenous desensitization, it may be more
cost-effective in terms of monitoring and staff requirements, and it may be
possible to perform in an outpatient setting. We propose our protocol as
a novel approach to furosemide desensitization therapy for patients with
non–life threatening reactions to furosemide. Further progress in the diagnosis
and treatment of hypersensitivity to sulfonamide drugs will require
identification of the major antigenic determinant and standardization of skin
testing and specific IgE testing.
I think we
should say good work to Dr Naureen Alim, then at Baylor College of Medicine
Houston, Texas.
If anyone wants to desensitize to a bumetanide allergy I think she is the one to contact for advice. She is easy to find via Google.
Here is another case example.
Desensitization
therapy in a patient with furosemide allergy
Allergy to furosemide is a rare phenomenon. Desensitization to this sulfa-containing drug has not been frequently performed. We describe a patient with severe congestive heart failure and type I allergy to furosemide. Because of the severity of her condition, we decided to use a rapid intravenous desensitization protocol. Following the desensitization, the patient was treated with intravenous and oral furosemide with a dramatic improvement in her clinical state. We suggest that rapid desensitization may be a safe and effective way of introducing furosemide to allergic patients for whom loop diuretics are urgently indicated.
In the case
of Acetazolamide, here is one published desensitization method:
Desensitization
to acetazolamide in a patient with previous antimicrobial sulfonamide allergy
Acetazolamide is a carbonic anhydrase inhibitor that is frequently used in the management of idiopathic intracranial hypertension. Acetazolamide is a sulfonamide agent; specifically, it is a non sulfonylarylamine, which lacks the amine moiety found at the N4 position that is seen in sulfa antibiotics.
Sulfonamide antibiotics contain a substituted ring at the N1 position that is thought to be the driving factor in immediate hypersensitivity reactions.
Although sulfa allergies are commonly reported, there is no evidence to suggest cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics. However, patients can report a history of allergy to both categories of drugs. We present a rapid desensitization protocol to acetazolamide in a patient with history of immediate hypersensitivity reactions to both a sulfonamide antibiotic and acetazolamide.
We formulated a 12-step intravenous protocol
that was performed in the intensive care unit setting (Table 1). Informed
consent was provided by the patient, and she tolerated the procedure well
without any adverse reactions. The desensitization procedure took 395 minutes
or approximately 6.5 hours. She was monitored overnight in the hospital and was
observed the following morning after taking 500 mg of acetazolamide orally to
ensure tolerance. She was thereafter able to continue her recommended dose of acetazolamide
without any issues to date.
Allergy to a sulfonamide
antibiotic does not always mean you will be allergic to the non-antibiotic sulfonamide
drugs.
Use of Acetazolamide in Sulfonamide-Allergic Patients With
Neurologic Channelopathies
The 3 patients had been considered for carbonic anhydrase inhibitor treatment but a pharmacist had refused to fill a prescription for acetazolamide for 1 patient and the other 2 patients were denied treatment because of the allergy history. All 3 patients were prescribed acetazolamide and had no adverse reaction. Two patients improved substantially and are continuing treatment. A review of the pharmacology literature suggests that cross-reactivity between antibiotic and nonantibiotic carbonic anhydrase inhibitors is unlikely. Moreover, a review of case reports does not suggest cross-reactivity. Previous reports in the ophthalmology literature also indicate that acetazolamide can be administered to patients with a history of antibiotic sulfonamide allergic reaction.
Conclusions
These 3 cases confirm
that the carbonic anhydrase inhibitor acetazolamide can be given to patients
with a history of allergic skin rash with antibiotic sulfonamide.
Acetazolamide has been used for the treatment of episodic ataxia type 2, with benefit in 50% to 75% of patients. In episodic ataxia type 1, acetazolamide was also effective in decreasing attack frequency. Acetazolamide is also effective in the periodic paralyses. Carbonic anhydrase inhibitors have been used to prevent altitude sickness, to lower intraocular pressure in open-angle glaucoma, and to treat refractory absence, myoclonic, and catamenial epilepsy as part of multidrug regimens. Acetazolamide has recently been used for hemiplegic migraine and idiopathic intracranial hypertension.
The lack of available clinical or pharmacological evidence to support cross-reactivity between sulfonamide antibiotics and acetazolamide lends supports to the use of acetazolamide to treat patients with episodic ataxia and periodic paralysis. Of our 3 sulfonamide-allergic patients, 2 improved in symptoms after treatment with acetazolamide and none of the 3 had a hypersensitivity reaction. We conclude that a sulfonamide allergy should not be a contraindication to treatment with acetazolamide in patients with neurologic channelopathies.
Acetazolamide and sulfonamide allergy: a not
so simple story
Allergies and adverse reactions to sulfonamide medications are quite common. Two distinct categories of drugs are classified as sulfonamides: antibiotics and nonantibiotics. The two groups differ in their chemical structure, use, and the rate at which adverse reactions occur. Cross-reactivity between the two groups has been implied in the past, but is suspect. Acetazolamide, from the nonantibiotic group, is routinely used in the prevention and treatment of high altitude issues and may not need to be avoided in individuals with a history of sulfonamide allergy. This review addresses the differences between the groups and the propensity for intergroup and intragroup adverse reactions based on the available literature. We also examine the different clinical presentations of allergy and adverse reactions, from simple cutaneous reactions with no sequelae through Stevens-Johnson syndrome and anaphylaxis, with risk for significant morbidity and mortality. We offer a systematic approach to determine whether acetazolamide is a safe option for those with a history of allergy to sulfonamides.
Sulfonamide-containing
antibiotics are the second most frequent cause of allergic drug reactions,
after the b-lactams (penicillins and cephalosporins). In one large study, the
incidence of reactions to trimethoprim–sulfamethoxazole (TMPSMX) was 3% of patients
exposed, compared with 5% for amoxicillin. The incidence of reactions to nonantibiotic sulfonamides
is not well established; it is clearly less than with antibiotics.
There
are several approaches to the use of sulfonamide drugs (specifically
acetazolamide) in patients with past reactions to this class of medications.
The choice of strategy depends on the type and severity of the previous
reaction, as well as the class of drug (antibiotic versus non antibiotic) and
the risk–benefit profile for the patient. However, regardless of the approach,
the risks of subsequent reactions cannot be completely eliminated, and a
thorough discussion between the medical provider and the patient should include
this point so that an informed decision regarding the use of acetazolamide can
be made. The safest approach for the patient with any prior reaction to a sulfa
drug, multiple drug allergies, or penicillin allergy would be to avoid all
drugs in the sulfonamide group, including acetazolamide.
Avoidance
of the entire sulfonamide drug group is warranted for individuals whose
previous reaction included a serious and/or life-threatening condition such as
anaphylaxis, SJS, and TEN. Any form of reexposure to the precipitating drug or
a sulfonamide in the same group is strictly contraindicated. Published evidence
has shown that SJS/TEN can recur with even minor reexposures and may be more
severe in the second episode. Even though SJS/TEN reactions are so far not
associated with nonantibiotic sulfonamides, because of the severity and
life-threatening nature of these reactions, a safe practice is to avoid all
sulfonamides in patients with past SJS or TEN from sulfonamide containing
medications.
This paper was published in a journal on high altitude medicine. That is why the suggested alternatives are staged ascents of the mountain and oxygen.
Conclusion
The first
key point is that you can have an allergy to sulfonamide antibiotics and have
absolutely no negative reaction to sulfonamide drugs like bumetanide and
acetazolamide (Diamox).
If you do
have a mild allergic reaction to a sulfonamide drug, there are desensitization strategies
that are proven to work in many people.
It looks
like rapid oral desensitization to bumetanide and acetazolamide is likely possible,
based on what has been shown possible with furosemide and a wide variety of
other drugs.
Clearly the
level of sensitivity and hence the nature of the allergic reaction can vary
massively from person to person, this is why rapid desensitization usually takes
place in hospital.
If you opt
for the slower process, much less is known, because it is not generally used.
If you did it in hospital it would require a very long stay and so would be
hugely expensive.
It is
suggested that slow drug desensitization (SDD) should be much more long lasting
and hopefully might become permanent – as is the hope for nut allergy treatment.
When posed
the initial question by our reader wanting to use bumetanide, I was thinking
along the lines of slow drug desensitization (SDD), because this is how you
would treat a pollen allergy. If rapid oral desensitization will work for taking
bumetanide once a day that would be great. To maintain the protection from
allergy it might be safer to take a small second daily dose.
Here is a
quick overview of desensitization options for sulfonamide allergy:
- Rapid Desensitization
(RDD):
- Faster process (hours)
- Temporary tolerance
achieved
- May be repeated if
needed
- Slow Desensitization
(SDD):
- Slower process (days,
weeks, or months)
- Might offer a greater
chance of longer-lasting
- Still requires close
monitoring
Important
Considerations:
- Always consult your
doctor: They
can assess your allergy severity, treatment options, and the suitability
of desensitization if necessary.
- Desensitization is not
without risks: It
requires careful monitoring.
I for one found this an interesting investigation and with promise for parents of those with severe autism who have been unable to trial Bumetanide due to a sulfonamide allergy.
Hopefully our reader Dr Antonucci will follow up on this and make a bumetanide desensitization protocol for those people with autism and a sulfonamide allergy. Maybe he has already done it. It looks very achievable.
Probably could use xolair too to help stop the allergic reaction.
ReplyDeletehttps://www.fda.gov/news-events/press-announcements/fda-approves-first-medication-help-reduce-allergic-reactions-multiple-foods-after-accidental
-Stephen
Peter,
ReplyDeleteWhen Monty gets a mosquito/bug bite does it get super inflamed? Just curious.
Stephen
Stephen, we have a lot of mosquitos at the moment and Monty is the least affected or bothered by them.
DeleteFor the rest of us, we use a topical antihistamine call Fenistel.
Interesting, when my son gets bit by mosquitos, he has a hyperinflammatory response and it swells up to the size of a quarter. Since I know he has an overactive immune system, that might just be an easy tell-tale sign for others too.
Delete-Stephen
Found that having good/high level of B12 in serum (we use MB12) reduces the mosquito bites. S.B.
DeleteHi, I've just found your blog and it's like hitting a gold-mine. I'm a medicinal chemistry student - and I believe I have ASD.
ReplyDeleteI have trialed many medications - all of which I researched and took to my psychiatrist - and have finally found a few that really help.
I'd love to get in contact if that's possible, I feel that I have a similar "mission" to you. I'm continuing to refine my meds and will probably continue trying new things for a long time - so far this approach has benefitted me.
I believe there absolutely are medications that can dramatically improve *some* of the symptoms of ASD, and that a large portion of these are not on doctors' autism drug list.
Please can we get in touch. You can email me at tankionlineemail@gmail.com (my anon email, dont want to put my proper one online).
This comment has been removed by the author.
ReplyDeleteI highly recommend that you look into memantine and propanolol - although it is a tough one, adding even more medications to the mix. I've noticed profound cognitive gains with both of these (backed by some evidence).
ReplyDeleteMemantine effectively reduces excessive glutamate signalling / excitotoxicity, with a similar mechanism to agmatine except much more potent... also has some dopamine agonist activity.
Propanolol is a strange one. Apparently beta2-adrenergic receptor antagonism improves functional connectivity in the (or at least some) autistic brains - leading to enhanced cognition.
Lastly - although I would not necessarily recommend this to your son, or children in general - kratom has been a complete game changer for my motivation, focus and brain fog.
Thanks for the suggestions.
ReplyDeleteMemantine is still widely used in autism. It was extensively trialed in the US and it failed to show an effect, so it is clearly only effective in a subgroup, but this is really what we should expect.
Propranolol can be beneficial at either low or high doses, depending on the individual. It has been well studied.
Kratom can be quite potent and has numerous effects. As you will know, it is potentially addictive, but is legal in most of the world.
Treating autism needs to be highly personalized. For my son agmatine is beneficial, but propranolol and memantine were not. In my non autistic older son and my younger son's assistant propranolol was effective for stress/anxiety before exams, driving tests etc. This type of use is well documented.
Hi Peter, Can we try little of Furosemide to the tune of 1mcg to see whether its allergic or do you think it should be done with Dr's perview.
ReplyDeleteThanks
Sudhakar
If you are seeking a Bumetanide alternative, I do not think Furosemide will work. A better option would be Torasemide, if you cannot obtain Bumetanide where you live.
DeleteMost allergic reactions to diuretics are mild and dose dependent. If you try a tiny dose you should be fine. Clearly the best option is to have medical support.
Hi Peter and the group, On a different topic, I saw the article https://neurosciencenews.com/psychosis-cognitive-network-27571/. What treatments would be the best to trial if child has asd/bipolar? Curious if this would change anything. Thanks. M
ReplyDeleteLithium carbonate is used to treat bipolar as a drug, while some people with autism find the OTC lithium orotate is helpful. The amount of actual lithium is very much lower in the supplement form.
DeleteIt is not uncommon to have autism plus features of bipolar.
Not many would admit to autism plus features of schizophrenia, but it certainly exists.
The genes involved in all these disorders and even ADHD and dyslexia etc are overlapping.
Bumetanide would probably work best. This article talks about psychotic breaks and mental illness.
ReplyDeletehttps://urldefense.com/v3/__https:/journals.lww.com/clinicalneuropharm/fulltext/2016/03000/treating_schizophrenia_with_the_diuretic.8.aspx__;!!IKRxdwAv5BmarQ!dlZhRKxtfRRFErIRqyFbpBA7Kd1zKY54tGAfaFm0UOwZ1Hu1kAAeSq4nFKJkUf4wGlkO_xd_T_Ka4YoPtwZC0JlBe7tRwlWOfg$
-Stephen
Hi Peter and other in the group who know about this worldwide study by roche?
ReplyDeletehttps://forpatients.roche.com/en/trials/neurodevelopmental-disorder/autism/a-12-week-placebo-controlled-study-to-investigate-the-e-88629.html
This drug targets the alpha 5 subunits of GABA A receptors
DeleteIt is called a PAM (positive allosteric modulator)
What that means is that the effectvof GABA on receptors that include specifically this alpha 5 subunit is increased.
This might improve cognition in some people. The trial is more about social behavior. They are trialing it on several groups. There is also a trial in Angelman syndrome.
I did write about this alpha 5 subunit in my blog a long time ago.
I thought that alpha 3 and alpha 5 were good targets.