Joe’s Note: Nowadays it seems like no one can agree on anything. But one thing I think we can all agree on is “rabies = terrifying.” If we’re being honest, most of us don’t even know what rabies really is. Is it a virus, parasite, bacteria, or fungus? Does it only come from bats? Is it deadly, or can it be cured? When someone says, “Rabies…,” our brain automatically thinks “danger.” But that’s about it. Most of us have a very superficial understanding of rabies (beyond the age-old image of foaming at the mouth), and for something so deadly, I think it’s important that we get a deeper understanding to help protect ourselves and our patients. So are you ready to become a rabies expert? Great, let’s start.

What is Rabies?

Rabies is a vaccine-preventable, zoonotic, viral disease affecting the central nervous system. It’s spread to people and animals via saliva, usually through bites, scratches, or direct contact with mucosa (e.g., eyes, mouth, or open wounds). Once clinical symptoms appear, rabies is virtually 100% fatal.

So yes, your feelings of “rabies=terrifying” are legit.

Waiting through a long incubation period be like… (Image)

In humans, rabies is generally composed of five different stages:

incubation,
prodrome,
acute neurologic period,
coma, and
death (or, very rarely, recovery).

The incubation period of rabies is the time between when a person is infected and when they start to show symptoms of illness. Unlike most other infections, the incubation period for rabies is rather variable. It usually lasts 30 to 90 days but can range from as few as 5 days to longer than 2 years after initial exposure. This long incubation period is what makes rabies so dangerous. This virus may continue to multiply for months before someone exhibits any symptoms!

The prodromal period is when clinical symptoms may first arise. Unlike the incubation phase, the prodromal period lasts for only 2 to 10 days. Generally, symptoms during this period are pretty nonspecific and mimic the normal signs and symptoms of any other viral infection. Patients in the prodromal period may complain of general fatigue, weakness, fevers, anorexia, muscle aches, headache, and some tingling/burning sensations at the bite site.

The acute neurologic period begins with objective signs of central nervous system dysfunction. This period can be broken down further into two different rabies classifications: furious and dumb rabies.

As the names clearly suggest, furious rabies (also known as encephalitic rabies) is characterized by hyperexcitability, agitation, aggression, and hydrophobia.

Okay, I want to pause here to give a totally irrelevant side note. Like three years ago I was scrolling through YouTube shorts, and this random video came up of a young hospitalized kid who was being asked to drink a cup of water. In this video, the kid kept trying to swallow the water but for some reason was completely unable to. So naturally, I did more research and learned that patients with rabies may experience hydrophobia.

Yes, I literally mean fear of water.

Turns out, when an individual with rabies attempts to drink water, the virus triggers involuntary contractions of the throat muscles, making it extremely painful and difficult to swallow. This can lead to perceived hydrophobia as the patient avoids drinking due to the excruciating pain it causes. Isn’t that so awful? Anyways, back to what we were talking about.

Dumb rabies (also known as paralytic rabies) is characterized by lethargy, depression, paralysis, and a dull or vacant expression.

Other symptoms that may present during the acute neurologic period include fever, paresthesias, muscle rigidity, focal and generalized convulsions, hyperventilation, and hypersalivation.

The acute neurologic period generally lasts 2-7 days in those with the furious subtype, whereas those with the dumb (or paralytic) subtype may experience symptoms for up to a month. At the end of the acute neurologic phase, periods of rapid, irregular breathing may begin, followed by paralysis and coma. Respiratory arrest may occur thereafter, leading to death.

Pretty terrifying and depressing all at once, isn’t it?

Luckily, in the United States, human cases of rabies are pretty few and far between. As in, the CDC reports that fewer than 10 people die from rabies each year. (Thank you, vaccination and public wildlife surveillance efforts!! Check out the graph to the right to see which animals in the US are common reservoirs, how many are carrying the virus, and how the numbers have shifted over the last 50 years…)

Globally, it’s still not incredibly common, but the absolute number is rather more scary. An estimated 59,000 people die from rabies around the world every year with ~40% of those being children under the age of 15 years and 99% of the sources being dog bites and scratches. Percentage-wise, small. Absolute number-wise, more than we’d like to hear (especially so many children!). Africa and Asia account for the majority of these cases.

Well now that it’s possible I’ve thoroughly chased you away from taking that hiking trip later this year… let’s talk management.

Is Rabies Treatable?

Okay so earlier I stated that the last stage of rabies is “death (or, very rarely, recovery).” So is rabies treatable?

The answer is…overwhelmingly no. Once symptoms appear, the mortality for rabies is nearly 100%. However, “nearly” is the keyword here. Over the past 50 years, it is estimated that rabies has caused approximately 2.95 million deaths worldwide. Yet, to date, there are approximately only 15-20 documented survival cases. That's about a 0.0007% chance of survival.

Yeah, the odds are not so good.

Not looking so good in the case of rabies… (Image)

Okay, so how did these 15-20 people survive then? Believe it or not, it’s still a mystery. There is NO clinically proven therapeutic treatment for rabies. That being said, there’s this “Milwaukee Protocol” that was developed after Jeanna Giese became the first known person to survive rabies. This protocol involves inducing a therapeutic coma and administering antiviral medications.

Unfortunately, the Milwaukee Protocol has been duplicated thousands of times to treat rabies, yet it continues to fail time after time. How Jeanna survived rabies is truly still a mystery. If you’re interested, I highly recommend reading her story here. It's quite fascinating.

Rabies Pre-Exposure Prophylaxis

So then, if we can’t cure rabies, what can we actually do? Well, we can most definitely prevent the transmission of rabies. How can we do that? You have two options. We can either give pre-exposure prophylaxis (PrEP) to patients at high risk, or you can administer post-exposure prophylaxis (PEP) in patients who had a potential exposure to rabies.

Let’s start with rabies PrEP. The majority of people in the United States have a low risk of contact with a rabid animal and never really need to be given PrEP. However, there is a small subset of people that may benefit from PrEP. The Advisory Committee on Immunization Practices (ACIP) categorizes patients into 5 risk categories: Level 1 includes patients with the highest risk while Level 5 are those with the lowest risk for rabies exposure.

To simplify who should get PrEP and who shouldn’t, take a look at the table below:

As you can see, the majority of us belong to risk category 5 and never need rabies PrEP. Therefore, it’s more important that we focus on post-exposure prophylaxis.

Rabies Post-Exposure Prophylaxis

Rabies post-exposure prophylaxis (PEP) is a medical intervention given after a potential exposure to rabies to prevent the disease from developing. It generally involves a series of rabies vaccinations and in some cases, an injection of human rabies immune globulin (HRIG). Even though deaths from rabies are rare in the US, an estimated 60,000 people here receive rabies PEP each year! So yes, good for pharmacists to know about this!

Rabies PEP is highly effective in preventing rabies if initiated promptly after exposure. In fact, there is not a single documented rabies PEP failure in the United States. It’s literally proven to be 100% effective in preventing the transmission of rabies.

So, who should get rabies PEP?

Well, there is this whole algorithm that walks you through each specific scenario and when rabies PEP should be considered.

Take a look:

Realistically, we always practice evidence-based medicine and should therefore follow that algorithm. However, I am going to be honest with you. We probably over vaccinate tons of people every single year with PEP. Think about it. A quick google search shows that ~7.7% of wildlife in the US tested positive for rabies. That means you have a 7.7% chance of getting rabies if you were bitten by a wild animal. That’s a pretty low risk.

However, given that rabies has a 100% mortality rate (and how terrifying of a course it is), we’re almost always going to err on the side of caution. Do we overtreat? Most definitely. But if it’s me, I am taking NO risk. Even if my chance of getting rabies was 0.001%. I still want that PEP.

Rabies Post-Exposure Vaccine & Immune Globulin

Okay so you have a patient who qualifies for rabies PEP. Now what?

Rabies PEP consists of two different interventions: rabies vaccine & rabies immune globulin. This can be confusing. So, I am going to simplify it for you.

Simply put, the rabies vaccine provides long-term protection by stimulating the body’s own immune system to create antibodies. On the other hand, rabies immune globulin provides short-term protection against rabies by giving the body antibodies to fight the virus.

The rabies vaccine should be given to ALL patients at risk for rabies transmission regardless of their rabies vaccine history. However, rabies immune globulin is ONLY recommended to patients who have NEVER been vaccinated against rabies.

Personally, I am a visual learner. So instead of throwing a bunch of paragraphs at you, here is a table I made that helps summarize the key differences between post-exposure vaccine and immune globulin:

One point I really want to hammer. For unvaccinated individuals, the rabies vaccine for PEP is a 4-dose series. The ENTIRE series must be completed to get full protection against rabies. Getting partial doses will NOT provide adequate coverage against rabies transmission. The four doses should be administered ON the days they're recommended: day 0, 3, 7, and 14. Waiting too long between doses can also reduce the efficacy of the vaccine and increase your chances of rabies transmission.

Other Considerations - Management of Animal Bites

So let’s say a patient comes to your hospital after a raccoon bite. You administer rabies PEP. Now what? While rabies prophylaxis should be on the top of your list, there are other interventions to consider.

We said earlier that rabies is generally spread to people and animals via saliva usually through bites or scratches. Even if the animal isn’t rabid, a bite can still become infected. This is where antibiotics come into play.

When you see posts about someone kissing their dog on the mouth or letting their dog lick their mouth. (Image)

Animal oral flora, much like humans’ oral flora, is generally polymicrobial. You have a bunch of different organisms including gram positive, gram negative, and anaerobic organisms. To make it even more confusing, the oral flora of animals may even differ depending on the animal species. For example, Pasteurella spp. is generally more of a concern with cat bites.

That being said, common offenders include Streptococcus spp., Actinomyces spp., Staphylococcus spp., Pasteurella spp., Capnocytophaga spp., Bacteroides spp., Fusobacterium spp.), and Moraxella spp. So what antibiotics should we start for animal bite prophylaxis? Depends on the severity of the bite.

Generally, most animal bites are minor and can be empirically treated outpatient with oral antibiotics. However, every once in a while you have that one patient that waited 3 weeks after the animal bite to come in. By now, their bite is grossly infected, and they look septic. In that case you need IV antibiotics.

When choosing oral vs IV therapy, here are the circumstances when IV antibiotics would be more appropriate:

Sepsis
Rapidly progressive (e.g., over hours) erythema
Progression after 48 hours of appropriate oral antibiotics
Deep-space infection (e.g., necrotizing fasciitis, septic arthritis)
Proximity of the bite to an indwelling device (e.g., prosthetic joint)

If your patient doesn’t meet any of the above criteria, then oral antibiotics are generally more than sufficient. So which agents should we start? Here is a list of the recommended and alternative regimens to start:

Generally speaking, the duration of antibiotic therapy is dependent on the severity of infection. If antibiotics are primarily being used for prophylaxis, then a duration of 3 to 5 days is recommended. If there is concern for an established infection, then treatment duration should be 5 to 14 days. Antibiotic therapy should be continued at least 1 to 2 days after symptoms and signs have resolved, usually not more than 7 days. Deep or complicated infections may require longer durations, particularly if a joint or bone is involved.

The tl;dr of Rabies for Pharmacists

Alright we reviewed a lot of information. Here’s a summary of all the important points we went over:

Rabies is a vaccine-preventable, zoonotic, viral disease affecting the central nervous system. Rabies is spread to people and animals via saliva, usually through bites, scratches, or direct contact with mucosa (e.g., eyes, mouth, or open wounds). Once clinical symptoms appear, rabies is virtually 100% fatal. In humans, rabies is generally composed of five different stages: incubation, prodrome, acute neurologic period, coma, and death (or, very rarely, recovery).

Unlike most other infections, the incubation period for rabies is much more variable. It usually lasts 30 to 90 days but can range from as few as 5 days to longer than 2 years after initial exposure. Rabies can be further classified as either furious (encephalitic) rabies or dumb (paralytic rabies).

Furious rabies is characterized by hyper excitability, agitation, aggression, and hydrophobia. Dumb rabies is characterized by lethargy, depression, paralysis, and a dull or vacant expression.

The Advisory Committee on Immunization Practices (ACIP) categorizes patients into 5 risk categories: Level 1 includes patients with the highest risk while Level 5 are those with the lowest risk for rabies exposure. Rabies pre-exposure prophylaxis (PrEP) is only recommended for individuals that belong to risk categories Levels 1-4. The general US population belongs to risk category Level 5 and does not need PrEP.

Rabies post-exposure prophylaxis (PEP) is a medical intervention given after a potential exposure to rabies to prevent the disease from developing. PEP consists of two different interventions: rabies vaccine & rabies immune globulin. Rabies vaccine provides long-term protection by stimulating the body’s own immune system to create antibodies, whereas rabies immune globulin provides short-term protection against rabies by giving the body antibodies to fight the virus.

The rabies vaccine should be given to ALL patients at risk for rabies transmission regardless of their rabies vaccine history. However rabies immune globulin is ONLY recommended to patients who have NEVER been vaccinated against rabies.

Empiric antibiotics should be considered for preventing infection secondary to animal bites. Animal oral flora, much like humans, is generally polymicrobial and is primarily composed of different organisms, including gram positive, gram negative, and anaerobic organisms. If antibiotics are primarily being used for prophylaxis, then a duration of 3 to 5 days is recommended. If there is concern for an established infection, then treatment duration should be 5 to 14 days (assuming no additional complications like prosthetics, etc).

Everything a Pharmacist Needs to Know about Rabies