Your Pet's Best Friend

Is there a good alternative to Immiticide treatment?

Eric writes:

Thank you for all the information regarding heartworm prevention and treatment. There is a lot of misunderstanding. We are an animal welfare group who took in a dog which tested positive for heartworms. The dog has received ivermectin weekly + doxycyline daily for two weeks, paused a week, and will receive another week of doxycycline.

A few studies conclude doxycyline + ivermectin kill adult heartworm: "Results indicate that the combination of these two drugs causes adult worm death." http://www.ncbi.nlm.nih.gov/pubmed/18433753 There is also internet talk of a "slow kill" method.

Do you have any advice for animal welfare groups or others with a budget that would not involve Immiticide? There are also such frequent shortages of Immiticide, it appears to be an annual event. Thank you.

For some reason, my reply is not posting to the original blog thread, so I am publishing it here.

Hello, Eric,

The American Heartworm Society has withdrawn its endorsement of so-called "slow kill" or "soft kill".

First, while some of the worms may die with long-term (like two years)administration of ivermectin and doxycycline, you cannot be certain of clearing the dog.

Second, the dog's problems with treatment arise from dealing with the death and movement of the worms within the pulmonary arteries.  We want to keep the dog's activity restricted until the dead worms have been dissolved by the body's defenders.

It takes at least five weeks for the dead worms to be cleared from the circulation.  With the Immiticide, we know when the worms will be dying (within a week), and can watch the dog accordingly. 

If you are treating long term with other medications, you would have to keep the dog's activity restricted for years, as you have no idea when (or if) the worms will be dying and moving.

The frustration with Immiticide shortage and expense is something I feel pretty personally.  While I have an adequate supply at present, I had none for several months.

My experience with humane organizations has been that resources are limited and must be allocated where they can do the most good.

When there was no indication that Immiticide would be available, the American Heartworm Society recommended monthly ivermecin (Heartgard, Iverhart, etc.) and 10 mg/kg of doxycycline twice daily for one month.  The doxy inhibits the Wohlbachia (beneficial symbiote of the heartworm)for an additional two months after giving it for one month.  Thus, they recommended repeating this at 3-month intervals.

If I were in a shelter environment, I would follow that protocol.  This is what one would do in the month prior to starting Immiticide treatment anyway.

The adopting owner just has to realize that he/she is taking on a bigger commitment when adopting a pet with heartworms.  There isn't a quick fix.

Thanks for reading and writing.

Pain after Heartworm Treatment

A reader writes in today:

Had our cocker spaniel treated 5 hours ago with his first shot.
For the past 5 hours, he can not get comfortable, fidgets, lays in unusual positions.

When walking, his right rear leg is toeing-in and his walks clumsily, often positioning that right foot too far under his body.
In just the last hour, he has started some toe-dragging with that right foot. Not severe, and he corrects upon moving further into the stepping process.

Also, he has started to drool excessively. Both ears are wet as if he drank from a flat bowl.

Have given him 2.5 mg Diazepam to try to make him more comfortable.

Forgot to mention ... the vet had to stick him twice unsuccessfully and then changed needles and successfully administered on the third try.
Do you think he is just experiencing more pain than usual because of the three 'sticks' at the site, or should we be concerned that something else is going on?

 My Reply:

Please call your veterinarian and let him/her know what is happening.

The medicine in the treatment (Immiticide) can cause a lot of inflammation at the injection site. This can occur no matter how smoothly things go and how little it seems to bother the dog at the time.

This can range from being absolutely undetectable to a dog that is crying constantly with pain. Diazepam helps with anxiety, but has no pain relieving properties to speak of.

Please contact your veterinarian about this, as human 0ver-the-counter products can be harmful to your dog. However, it sounds very much like your dog needs pain medication.

The pain usually subsides in a couple of days, and most dogs don't have this type of reaction, but the ones that do get painful do need some help.

The difficulty in walking may indicate that the inflammation is causing enough swelling to put some pressure on a nerve root.  This can be very temporary, but certainly needs to be addressed.

Call your veterinarian and report this situation.  He/she will decide what anti-inflammatory or pain-controlling measures are needed to help your dog.  He/she can't help if they don't know about it.

What to do now that Immiticide is in short supply.

A reader writes in:

Hi. I have a 12 year old mixed breed who has been on Heartguard preventative most of his life. Unfortunately, he recently tested positive for heartworms. We live in the South, and he is an outside dog.

Anyway, the vet said because of his age and the expense that we should just give him prednisone, doxcycline, and sentinel, and that he would eventually suffer from congestive heart failure.

Will this regimen even help? What exactly will it do? What is the pattern of treatment? The vet mentioned to give him the prednisone alternating months. What do you recommend for the frequency of these meds?

My answer:

Heartworms actually are mostly located in the pulmonary arteries, the blood vessels that take blood from the right side of the heart to the lungs to get oxygen. Their presence in these tubes interferes with the circulation in the lungs, and makes the arteries themselves inflamed. This can cause swelling, which narrows the opening in the artery, further interfering with this blood circulation.

Even when there are no worms in the heart yet, this difficulty in the lung blood vessels makes it more difficult for the heart to do its work. This causes excessive wear and tear on the heart.

Doxycycline inhibits a microorganism called Wohlbachia that benefits the heartworms (much as the "good" bacteria in our intestines help us). When the dog takes doxycycline, the heartworms become weaker and physically smaller. Thus, they cause less interference with the dog's circulation. Doxycycline is also a little bit of an anti-inflammatory medicine.

Prednisone is a form of cortisone, which is a potent anti-inflammatory medicine. If the worms are causing swelling of the blood vessels (making the opening smaller, and more difficult for the heart to work against), the prednisone can open things up again.

There is currently a severe shortage of Immiticide, the drug used to kill adult heartworms. Until it becomes available again, the American Heartworm Society is recommending that dogs be managed in the way that your veterinarian is recommending.

I think that your veterinarian's recommendations are very reasonable, considering your circumstances. If you have more questions, please take the time to let him/her know. Many times we think that we are great communicators. If nobody calls back, we just assume all their questions have been answered. If you have more questions, I'll bet that your veterinarian will be happy to discuss them with you.

AHS offers guidance in face of Immiticide shortage to treat heartworm infection

Aug 11, 2011 DVM NEWSMAGAZINE

National Report -- As a shortage of the heartworm treatment Immiticide® looms, the American Heartworm Society unveiled an interim management plan for veterinarians yesterday.

"With Immiticide unavailable, veterinarians will need to take steps to carefully manage their heartworm-positive patients," says Wallace Graham, DVM, president of AHS in a prepared statement.

Crafted by AHS' Board and Scientific Committee, the management plan calls for veterinarians to:

· Reduce potential pathology from infection

· Maintain the health of the heartworm-positive dog until it can be appropriately treated

· Prevent additional heartworm infection of the dog.

Management steps include:

· Verification of heartworm status

· Pretreatment of heartworm-positive dogs to prevent shock

· Careful administration of a macrocyclic lactone heartworm preventive, followed by clinical observation for at least eight hours

· Continuous administration of a heartworm preventive on the regular dosing schedule

· Administration of doxycycline on a one-month-on/two-months-off schedule

· Restricted activity and exercise of the heartworm-positive dog throughout the management period · Medical treatment of symptomatic heartworm infection to relieve signs of respiratory disease, with surgical options weighed for dogs exhibiting cardiovascular compromise

· Retesting for heartworm status before treatment with adulticide treatment once the product is again available.

The goal, Graham says, is to manage the patient until Immiticide becomes available.

Earlier this week, Merial sent a notification to veterinarians that the drug melarsomine will be in short supply due to technical production problems at a plant. Click here for the AHS Guide to Heartworm Management During Adulticide Unavailability.

From Dr. Mobley:  Now they're telling us we won't even be able to get Immiticide by begging for it.  What's the world coming to?

Demodex Mites live in the hair follicle.

This little guy has localized demodecosis.  He doesn't look bad at all, not like generalized demodecosis (aka, "red mange").

This is the "spot case" type of demodectic mange that almost always is self-limiting, i.e. the dog recovers whether you treat him or not.  Since I've already talked about this at length in previous posts, why bother to bring up this little guy today?

He's got a couple of spots of hair loss, but they really aren't bothering him much.  He came in for his puppy booster vaccinations and the owner hadn't really paid much attention to the spots.  I found them during the physical exam, asked the owner if there were any scratching or chewing, and and there wasn't.

You ALWAYS need to do skin scrapings when you see pets with skin problems, even when you are "sure" that it couldn't be mange mites (because sometimes it is anyway).

The cool thing is what I found on the skin scraping.  In active cases of demodectic mange, you usually find a lot of mites, and in varying life stages: eggs, larvae, nymphs, adults, little family groups, and so forth.  In cases that are recovering, you may find only one or two mites, or none at all.

What you usually don't see is what is in this picture.  I have performed countless skin scrapings in the last 33 years and have never seen this before.  Neither have the parasitologists on Veterinary Information Network.  We know that the mites live deep in the hair follicles, but seeing mites within the hair itself is pretty cool.

Immiticide Shortage Now Under Control... Sort of

Well, I've been remiss in not bringing the Immiticide status report up to date since my last post.  The FDA has granted a provisional approval to the European supplier of the raw materials for melarsomine.  This apparently falls under some sort of "compassionate use" guideline.

The official line now is that we still cannot just buy it from our distributors to keep in stock and have on hand.  That would be too easy.  However, if we call Merial directly, and order product for a specific patient (name, date of birth, weight, serial number, etc.), we can buy as much as we need. 

The thrust of this is that the drug is no longer being rationed for the treatment of sick dogs only.  Now we can go ahead and treat the dogs that missed a pill here and there, or where the preventive simply was not 100% effective.

So, we're working through our backlog of about 15 dogs since the first of the year, plus three more this week.

Heartworm Treatment Drug Shortage Update

You may recall that I posted some time ago on the shortage of Immiticide, the only drug approved to treat dogs for heartworms disease (that is, to kill the adult heartworms).  They were going to have it all fixed by the end of March.

Well, now, last week it was after "March 31st", which was when I had been told previously the shortage would be resolved. I called Merial, and the first layer of staff said, "Not yet; they said late March or early April." The "early April" was new to me. I asked to speak to someone who actually knows what's going on, and she bumped me up to the next tier in the hierarchy.

That person gave me the same story. I said, "Look, I've been a good boy, and I haven't pretended my patients have clinical signs when they don't. I haven't tried to order product for dogs that are apparent lack of efficacy cases. I do have 12 people breathing down my neck wanting their dogs treated. It would help if I could just get a straight answer for them on what the problem actually is. Did you try to move the factory to Pakistan and the Taliban took it over, or what?"

I still didn't get a straight answer, but she asked how many dogs I had and what they weighed, and sold me enough Immiticide to treat them.

Of course, I've got four new dogs to treat since then that weren't on the original list.

If we can get every detail of Tiger Woods' indiscretions, can't we find out what is actually going on at Merial? And where is Osama bin Laden? Does HE have the Immiticide?

Well, here's the news from Veterinary Information Network today... finally:

Merial Statement on availability of IMMITICIDE® (melarsomine dihydrochloride)

Recently, Merial informed veterinarians that our heartworm treatment product, IMMITICIDE® (melarsomine dihydrochloride), was in limited supply because the active ingredient was no longer available from its manufacturer—the only US source of the compound.

Merial has now identified an alternative supplier for melarsomine—one that already produces it for the European and international markets. However, gaining US regulatory approval for the new manufacturer will take time. In the meanwhile, Merial has instituted a temporary measure to extend the supply of IMMITICIDE and continue to make it available to veterinarians.

Through a restricted distribution program initiated in agreement with the FDA’s Center for Veterinary Medicine (CVM), veterinarians who have an immediate need to treat a dog with heartworm disease will be able to purchase IMMITICIDE containing melarsomine manufactured by the alternate supplier. This product must be purchased directly through Merial. It will not be available through Merial’s distributors, nor will it be available for purchase to stock clinic inventories. Veterinarians who wish to purchase IMMITICIDE should call Merial Technical Solutions 

Merial is continuing to work closely with FDA-CVM and the new melarsomine supplier to gain FDA approval for this alternate facility and return to full supply of IMMITICIDE as soon as possible.

Not that this helps me or my patients, much.  I still don't feel like we have the full story.  They sell this stuff like gangbusters.  Why would the supplier of the raw ingredient shut down when they have a guaranteed market?  I still think Osama bin Laden may be involved somehow.

Heartworm Treatment Drug Shortage

I treat a LOT of dogs for heartworm disease.  The treatment is not complicated to perform, but managing the dog's six to ten weeks of convalescence can be quite complicated. That's why I took the trouble to produce my own brochure to help explain the process to clients.  There are lots of ready-made sources of information on the disease process, but it was a little harder to find an explanation of the nuts and bolts of what goes on inside the dog -- why you might have complications, and how to recognize them, and what to do about them.

Since we treat a lot of dogs for heartworm disease, we use an awful lot of this medication.  Immiticide is the only drug available to treat dogs to kill the adult heartworms.  It is made by only one company, Merial. [There was an older drug called Caparsolate - Merial bought the patent and deep-sixed it.] There are five little vials in the box.  Once you mix them up, they are only good for 24 hours, so there's not a lot of medicine in each vial -- you wouldn't want to waste it.  An average big dog will take 3 or 4 vials to treat.  A really big dog could take five.  It's not uncommon for me to go through fifteen bottles in a week.  Whenever my stock drops below fifteen bottles, I re-order.

That is, I try to re-order.  While I used to order everything by phone (I'm such a Luddite), I recently started ordering on-line from my main distributor.   I was really hacked off when Immiticide would not come up on my screen Wednesday evening, and I sent them a very sharp e-mail.  I had to order by phone the next day.  That is, I tried.  My distributor apologized, saying that there's no problem with the way I use their website -- they just cannot sell the product right now.  There is a shortage, and I would have to order direct from the manufacturer. 

Today I received a form letter recapitulating the information I got when I contacted Merial yesterday.  "As a result of unforeseen technical difficulties during a planned manufacturing site transfer..." [overseas, perhaps?  Maybe they are relocating production to Afghanistan?]  Anyhow, they are rationing the stock they have, as they don't expect to be back in production before APRIL.  If I have a dog I need to treat right now, and I'm totally out of medicine, and I beg really hard, and if I'm a really good boy for Christmas, they might sell me one box of five bottles.  BUT ONLY ONE BOX AT A TIME, and only if I can prove I really need it, and only once per week. 

So now I have to beg Merial before I can schedule a treatment.  I'd love to know what those actual "technical difficulties" are... and where they are relocating the production site.

Could I just give preventive medicine, instead of treating my dog for her heartworms?

So here's another set of questions about heartworm treatment where the answer bears repeating.  This is a continuation of a dialog that began in a previous post about heartworm treatment.  This fellow is out east and has adopted a stray, and unfortunately, the dog has heartworms.  At present, he doesn't feel that he can take on the full recommended heartworm treatment with Immiticide to get rid of the adult worms.  He has questions about the alternative of just putting the dog on heartworm preventive and trying to "hold the line".

Have you seen young, lightly infected (class 1) dogs overcome a few years of heartworms (maybe
 living 2-4 yrs with them and then having no more adult worms due to preventative) and still live decently long lives?

  Or is it just ridiculous to think that preventing more adult worms to come and slowly suppressing the ones she has already is okay and not cruel?  I worry that just giving her Ivermectin regularly and some doxcycline will be good, but not great, and that years will be taken off her life due to heart damage.
 
  Finally, this is an extremely active dog.  She loves to run, jump, and play with our retriever.  I
  haven't heard her cough or seen her severely out of breath, but it seems this physical activity is not ideal.  How much should we cut back?  Can she play for a few minutes, or is any exertion just adding more of a chance of heart/artery damage?

 Sincerely,
Jason

Hello, Jason,

The experts say that the severity of disease (actual structural damage resulting in decreased function and shortened life, versus just the presence of worms) is due as much or more to a dog's activity level as to the number of worms present.

Unless there are a huge number of worms (as in a dog that has died from the disease, which would be the picture at the top of the post), they really aren't in the heart, but rather in the pulmonary arteries, those vessels coming from the right side of the heart to the lungs (to get oxygen).  If the dog is athletic and active, a more turbulent flow of blood is generated in the arteries by the higher blood pressure and more rapid heart rate.  This beats up the inside of the arteries by whipping the worms around.

A relatively small number of worms can thus cause more damage in the athletic dog than would a larger number of worms in the couch-potato dog.  The couch-potato dog takes it easy, has a slow heart rate, lower blood pressure, and so the worms are just floating lazily in his blood vessels.  They aren't getting whipped around.

When the arteries get beat up, they become inflamed, and they swell.  The swelling of the walls causes a narrowing of the open space in middle.  This restricts blood flow, causing higher blood pressure in the lungs, and creating increased resistance to the heart's effort to pump blood through the vessels.  The heart eventually begins to wear out from constant overwork.

The more often, and more vigorously a dog exercises, the more likelihood that even small numbers of worms will eventually cause significant damage.  Unfortunately there is no way to say what magic number of worms will be safe, and even if there were, there's no way to count the worms (at least while the dog is alive). 

In our area, you can count on an outside dog having some heartworms by the age of one year if he receives no medication.  I have seen many dogs who received no heartworm-preventive whatever lead apparently normal lives until the age of 3 to 5 years, having good exercise tolerance and looking great.  Then they begin to show outward signs of decreased exercise tolerance, which progresses eventually to congestive heart failure by less than half of a normal life-span.

SO, if your dog is young, healthy, has very few worms, and you keep giving the ivermectin each month so that he doesn't get any additional worms, then yes, she has good odds for a good quality of life for several years.  If she were older, or has more worms, then not such good odds.

So, "good odds" of a good life, but no guarantees.  What did Dirty Harry say?  "Do you feel lucky, punk?  Well... do ya?"

It surely would be better to treat the dog for the adult heartworms.

Are Heartworms getting worse? A Seminar: Part 6 of 6

Doxycycline’s Role in the Treatment Process

This also relates back to our problems with heartworm treatment.

Doxycycline kills L3 and L4 larval stages of the heartworm, and it decreases embryogenesis (the production of microscopic baby heartworms -- microfilariae).  It has intrinsic anti-inflammatory effects.  It greatly inhibits Wohlbachia, which is a symbiotic rickettsial organism needed by Dirofilaria immitis (the canine heartworm) to survive. 

When you treat with Doxycycline at 10mg/kg/day for 30 days, it will clear microfilariae and it will shrink adult worms.  [Doses twice this high have been recommended, but some dogs do not tolerate the dose as well.]

We know that more inflammation is produced in the dog when worms die with Wohlbachia present, than in dogs with worms where the Wohlbachia have been suppressed with Doxycycline.

Clinically the effect is not very great in dogs that have few worms and no microfilariae. [Dogs who have been taking year-round preventive medicine, but develop a positive blood test]  In dogs that have not received preventive medicine, who have more worms present, the beneficial effect is more noticeable.

It would be advisable to use Doxycyline in dogs that one suspects to have a significant worm burden and who are not in need of immediate treatment.  It is combined with Ivermectin given weekly during the month of Doxycycline treatment, prior to giving Immiticide.  This should eliminate microfilariae, shrink the adult worms, and reduce the amount of inflammation associated with the death of the adult worms.

Conclusion

This is not a very satisfying conclusion to my seminar, but this reflects the fact that I don’t have a good answer to my problem.  I don’t know the cause of the apparent preventive medicine failures, nor why it is more difficult to eliminate adult worms and microfilariae than it used to be.  I'm starting to get used to it, but I've become used to dog-bites, too, and I don't like that either.

I don’t have a strategy to improve the situation, which is why I was eager to share experiences and information with the other veterinarians and the parasitologists.  I’m looking forward to seeing what the future holds here.