148. Rat Bite Fever: Streptobacillus & Spirillum

Rat bite fever: Neve seen it, probably never will, here's a podcast episode on it anyway. 

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Jame 0:18

Callum, how are you doing?

Callum 0:20

Good. I'm, I'm, I've got this drink here

Jame 0:23

Yes, I can see that,

Callum 0:25

I'm thinking about drinking it, but, I'm mu- mulling it over,

Jame 0:31

Aha

Callum 0:32

whether to drink it or not, 'cause it's not a normal drink, it's a shot. So you could say that 'cause I'm mulling it over, I'm a shot muller

Jame 0:39

I don't understand

Callum 0:41

Which is funny because we're talking about an organism discovered by German microbiologist H. Schulten in 1914

Jame 0:48

It's a two-level removed pun. So the only people who will get it are the people who have actually read the prep notes in advance of me releasing the episode. So I'm literally the only person that will get this pun.

Callum 1:01

I think that's, I think that's quite normal.

Jame 1:03

all you're bringing to the table,

Callum 1:04

I think this is, it's quite normal that you're the only person that gets the pun, if I'm quite honest

Jame 1:09

what a coincidence that is, 'cause what are we discussing today?

Callum 1:13

We're talking about rat bite fever

Jame 1:16

you're

Callum 1:16

I'll be honest, Streptococcus and spirillum I didn't come up with a pun for those. So if you, dear listener, come up with a pun for either of those, which probably isn't that hard actually please do send them in

Jame 1:28

Yeah, you'll run rings around Callum. You'll really spiral him. Anyway, we're talking about rat bite fever which is caused by two organisms, streptobacillus and spirillum, which as far as I can tell have virtually nothing to do with each other except that they both live in a rat's mouth

Callum 1:45

Yes, and spirillum is somewhat, mm, controversial. But let's, let's talk about streptobacillus, which is more straightforward

Jame 1:53

Yeah. Okay. Streptobacillus let's give the overview Cal. So this is a genus of fastidious gram-negative bacilli. There are five species. There's the type species moniliformis, which is the one that causes most rat-bite fever. And I wonder, Callum, if I will tell you the species name, you can guess what kind of animal it lives in. Canis,

Callum 2:14

Dog.

Jame 2:15

felis,

Callum 2:16

Cat

Jame 2:17

ratti,

Callum 2:18

Brat?

Jame 2:18

notomys

Callum 2:20

Nothomyzis. Is that an animal?

Jame 2:21

Oh, Callum, clearly it's something with the Notacord That's one for the cladists among you. And it was discovered in 1914 from a man who had been bitten by a rat by German microbiologist H. Schottmüller, who described it as Streptothrix muris-ratti. And then in 1916 in the USA, Streptococcus moniliformis was determined to be the cause of rat-bite fever. And in 1925, uh, Streptococcus was recultured in a blood culture isolate from a lab worker with fever, rash, and arthritis. then in 1926, multiformis was grown from the blood of patients during an epidemic illness resembling rat-bite fever in Haverhill, Massachusetts. It was later determined that Haverhill multiformis and Streptomyces moorei ratti were identicals to Streptococcus moniliformis, and so it was given that name

Callum 3:15

isn't the history of this just fascinating?

Jame 3:18

It is really, yeah. I'm really liking the history bits of this. But Cal, why don't you tell us a little bit about spirulum? So I've decided that I'm gonna be Captain Streptococcus and you're gonna be Captain Spirulum

Callum 3:29

That's the rubbish one.

Jame 3:30

of the show.

Callum 3:31

So spirillum it's much more common in, in Asia and also Africa. And it... This is a short and thick and motile spirochete, so spiral-shaped. It's an obligate microaerophile, so a bit like Campylobacter. And they have these bipolar flagellar tufts. And history, in the 19th century, it was discovered by somebody called Carter, and in the early 20th century specimens with patients with the Sudoku form of rabbit fever were shown to contain spirochetes that could infect guinea pigs. And this was identified as Well, it was initially called Spirochaeta, Spirochaeta morsus muris or Sporozoa muris. And in 1924 it was renamed as Spirillum minus

Jame 4:20

And why is this controversial, Cal?

Callum 4:22

It's controversial because it has never been formally categorized into more modern taxonomy because it's difficult to identify. And like many spirochetes, quite difficult to culture is my understanding. So whilst it's mentioned in Mandell's and there's plenty of literature about it I think there's a bit of debate about what it actually is

Jame 4:45

Yeah. You, i-interested listeners should have a look at the Wikipedia entry for spirulum minus, which is very scathing as to whether or not it exists at all, which I think is a little bit harsh, but certainly it's not got as heavy a, a base as streptobacillus is for example. So let's talk about where they are and from now on, e-everything that we say applies to both of these things unless we specify otherwise. So they are mostly from the animal mucosa, but particularly rat mucosa. The upper respiratory tract and the mouth of rats are the main places where you will find these things. they're rarely a cause of otitis media in rats, but i-in inoculation w- is mostly asymptomatic to give you an example of how common they are, Spirillum minus can be identified in about a quarter of all rat mouth mucosa. So the risk factors are contact with rodents, but also cats and dogs. The most high-risk injury would be a bite, but also scratches or anything where you come into contact with rat urine, would be a risk. And the infection tends to happen in places that are dense urban areas with poor sanitation. Places where you could come into close contact with rodents, sometimes without even realizing it, so you get contact whilst you're asleep for example. And the other risk factors are animal workers, so think veterinarians, pet shop owners, people like that. There are some rare cases of nosocomial transmission, and there's an outbreak form where rat urine has contaminated something in the food supply. This is the Haverhill form of rat-bite fever, and that's almost invariably Streptococcus. And there have been noted outbreaks associated with contamination of turkey or milk or the water supply with rat feces resulting in small epidemics

Callum 6:42

And we know it's called the Haverford or the Haverhill Form because of that instance in 1926

Jame 6:48

Yeah, that outbreak in Haverhill, Massachusetts. A load of stuff got named because there was an outbreak of something in Massachusetts, I'm I'm thinking. But let me tell you about the Haverhill form, which is also known as epidemic arthritic erythema,

Callum 7:02

Mm-hmm.

Jame 7:02

you most of what you need to know, to be honest. This is the streptobacillus moniliformis form of rabbit fever and therefore it is mine to describe to the listener. It's

Callum 7:13

Wait,

Jame 7:13

about...

Callum 7:13

wait. I thought you said everything... Oh, this is specific to that, but you just described the stuff that was for both things

Jame 7:18

Yeah, but now I'm talking about the two different forms of rat-bite fever, which are the Haverhill form and the Sodoku form

Callum 7:26

Okay

Jame 7:26

Haverhill form is caused by Strep to Bacillus moniliformis and the Sodoku form is caused by Spirulum minus. And so let me tell you about the Haverhill form now. So the incubation period is about three to 10 days, so call it a week or thereabouts, and it will onset with chills and a fever, and the fever will tend to subside at about three to five days, but will irregularly recur over the next few weeks. About 50% of people will get headache, vomiting, muscle aches, and joint aches, and the joint aching is migratory. At about two to four days, you will then get a rash, which tends to be maculopapular and favors the periphery, so the hands and the feet. And about 50% will get a arthritis, again, at the two to four-day mark, which will, in some cases, become a septic arthritis. And if it is a septic arthritis, it will favor the knees more than the other large joints In children, there is a presentation with fever, weight loss, and diarrhea, which you don't really see in the adults. a point to note about the Haverhill form is that you get more nausea and vomiting, more pharyngitis, more kind of upper respiratory tract symptoms, and a bit less lymphadenopathy compared to the Sudoku form. And that, I think, is related to the method of inoculation, which is usually contamination of food. All those symptoms that I mentioned tend to subside by about the two-week mark, but the fevers come back, and the arthritis can also last. And then there, there are some complications which are usually related to the streptococcus becoming bacteremic, and that's endocarditis, pneumonitis, and meningitis. If you don't treat this, the mortality is about ten percent. And an interesting thing is that about a quarter of them have a false positive syphilis RPR. if you go looking for syphilis, 'cause of course fever and a bit of a rash can look a bit syphilitic, you may get a positive RPR, but that does not necessarily mean that this is Treponema pallidum callum, why don't you take us through the Sudoku form?

Callum 9:30

It was great. I I learned a lot there. I've never seen a case of rat-bite fever.

Jame 9:34

Me neither. Me

Callum 9:34

oh, well, that exposes for the frauds we are. The sudoku form. Now if like me, you're mishearing this Jim has pointed out this isn't to be confused with sudoku, which is a contraction of a longer Japanese phrase, which I'll attempt, but I apologize in advance.

Jame 9:54

Sujiwa dokushin ni kageru

Callum 9:56

i'll just stub that in as if I've said it. Thanks, Jim.

Jame 9:59

Thank you very much

Callum 10:00

which translate to the digits must be single.

Jame 10:02

anyway, now that we've alienated every single Japanese listener why don't we go on to describing the Sudoku form in,

Callum 10:08

Well, first, I think it's interesting to learn

Jame 10:11

tell me what Sudoku means

Callum 10:13

so means rat and doku means poison. So rat poison. I love it when things are named for what they do. It's brilliant. So the incubation for this is seven to 21 days, although reported up to 24 so the symptoms are fever, which usually lasts two to four days and then dissipates and then recurs, and it's reported around four to eight weeks. Malaise, headache, and skin ulceration at the bite site, and that's usually one to four weeks following the bite. You can get a rash of plaques which are purple or red, and they're usually at the extremities, on the face and the scalp. You can also get lymphangitis or lymphadenopathy, and rarely there's myalgia or arthralgia. So it differs quite a lot from the Haverhill form. Complications of this form include soft tissue i-infections and v-abscesses which can be solid and green. You can get septic arthritis, pneumonia, hepatitis, nephritis, meningitis, endocarditis, myocarditis, pericarditis. And the untreated mortality is reported to be six to ten percent, and of note, around fifty percent have reported to have a false positive syphilis RPR. So it could be a useful diagnostic test actually to do your, you know, full syphilis testing and do an RPR.

Jame 11:34

Yeah if you can interpret it in context, although I suppose the history is probably more important here, where they went and what they did and whatnot. Yeah. And if listeners are interested in a comparison, I've taken this from, I think Mandel's. There's a little table saying what is a feature of which variant of rat-bite fever, and so you can go into the prep notes and have a look at that for yourselves. Cal, do you want to take us through the microbiology?

Callum 12:01

Yeah, so we're talking here about Streptococcus moniliformis which is a bit more straightforward. I'll do it though

Jame 12:06

you are the microbiologist of the podcast, so I feel that this is more your baby.

Callum 12:12

Technically. Although I,

Jame 12:13

do treatment for both.

Callum 12:14

I often think, Jane, that you,

Jame 12:16

Deal? Deal?

Callum 12:17

yes, that's a deal. That's a deal. I I think you know quite a lot of microbiology, so you know, you, you'd be welcome any time to join us. Join us

Jame 12:25

Never bow to the dark side

Callum 12:27

So the organism this is a pleomorphic gram-negative bacillus in chains it's 0.3 to 0.7 micrometers wide by one to five long. It's fastidious. It's microaerophilic. Doesn't form spores. It doesn't have a capsule, and it's non-motile, and it grows on an enrich, enriched media. So you know, you could grow in broth, enrich of serum or something called trypticase soy agar, which I've never heard of before

Jame 12:54

Okay, good. Me neither

Callum 12:56

And then on, on a plate, the colonies are circular, grayish, and shiny. They're quite small at three days, so one to two point five millimeters. Are non-hemolytic and it will reduce nitrate to nitrite, so it's nitrate positive, and it's negative for catalase, oxidase, and indole. So you know, nothing that, that descriptive. And then usually you would speciate this when you culture it from blood or joint fluid. Obviously, you'd usually do Maldi-TOF, although the Maldi-TOF is limited by what's in its database. 16S PCR might be another sort of modern form. And from Mandel how they say to identify it obviously without using these modern techniques. So you could either directly visualize a pleomorphic bacillary organism in a Giemsa stain, which is quite unusual, or or an acridine orange or Gram stain smears. But generally you're trying to culture it so rather than relying on a, on a microscopy. And there's an image in the prep notes from UK SMI ID1, which is Introduction to the Identification of Medically Important Bacteria and Fungi from Culture, which is actually quite a useful overview if you're new into microbiology. And there's a whole host of these sort of small pleomorphic, quote unquote, "weird little gram-negatives" that can be quite hard to tell apart. And Streptococcus falls into that category. So identifying these in the laboratory can be challenging

Jame 14:26

And relies a lot actually on the history doesn't it, Cal? 'Cause if I look down that list of things, I'm thinking about what else is in this list, Bordetella. Bordetella pertussis. I'm looking at the clinical syndrome there to make that diagnosis, and same with Bartonella and three of the HACECs are in there, Aggregatibacter, Eikenella and Haemophilus, things like that. You would be thinking about how the patient is presenting, which makes the role of the microbiologist as a history taker all the more important What about spirulum minus?

Callum 14:56

Well, it's never been grown, so there you go.

Jame 14:58

No.

Callum 14:59

Who knows?

Jame 14:59

you wanna know why we don't know a lot about it? Because we can't grow it in the lab, that's why.

Callum 15:03

Yeah. So you can, you can try and diagnose it from the clinical features that we've described and from seeing spirochetes on blood or joint fluid in the dark field microscopy. And when you look at it as a short, thick, gram-negative spirochete. And xeno-diagnosis was used historically. So you look, we heard the story about the guinea pigs earlier on

Jame 15:23

Yeah, but I don't think you would do that now. I don't think anybody would bother seeing as it is so easy to kill both of these organisms and I take treatment Cal

Callum 15:32

Shall I let you? Yeah, I'll, I'll unleash, you on treatment

Jame 15:35

Thanks, pal. So the number one treatment for this historically has been penicillin IV penicillin G, although i'd be astonished if in modern times we didn't just use amoxicillin or penicillin V

Callum 15:46

No, this is one of... It's actually one of those rare organisms that knows the route that the drug was administered from. You know those ones? It's like, "Oh, it's just only oral penicillin that's made its way into the bloodstream. I'm not responding to this."

Jame 15:58

it does not work. Yes, of course. Sorry, I forgot about that. The, the treatment is usually with a penicillin, and it's usually for seven to 14 days. Now, these bugs are not important enough not common enough to be able to get their own trial I think. So I know that you'll get a seven versus 14-day study. I would be astonished if seven days wasn't enough to kill these things. But anyway, penicillin would be the choice. For a spirillum minus infections, you sometimes get a Jarisch-Herxheimer reaction. And if you can't use a penicillin, then tetracyclines are the second-line option, usually doxycycline, not least because it's, widely available all over the world. And then you can use virtually every other beta-lactam. You can use clindamycin, is interesting, Callum. Why?

Callum 16:45

No idea

Jame 16:46

Let's go down the list. You can also use macrolides. You can also use nitrofurantoin, bacitracin, or vancomycin/ticarcillin. And why is that interesting?

Callum 16:56

Oh, I see what you're getting at.

Jame 16:57

Yeah

Callum 16:58

because these are normally gram-negative organisms, and we usually think of clindamycin covers gram-positives and vancomycin, teicoplanin only covers gram-positives

Jame 17:07

Yeah, but it's a lie. And they do cover gram-negatives, just not many of them. these are examples of those that there have b- there's been demonstrated use of those with clinical cure. And I don't know that the evidence for this is particularly sharp. It's probably, mostly Petri dish inferences and whatnot. But anyway, it was everywhere I looked. The CDC, who have a fantastic website on this phenomenon, by the way and in Mandel's as well. And then in the very rare cases where you've got endocarditis, they recommend penicillin combined with gentamicin, for which there is, of course, absolutely no trial evidence whatsoever. But you use pen and gent for other conditions that cause endocarditis, and it works, so I imagine it would work for this too. And I had a look for EUCAST breakpoints, Callum. There are none. I had a look even for ECOFFs against Streptococcus and spirulum, and there are none, at least in the EUCAST database. And I looked for resistance mechanisms, and I found no published evidence of any. So I'm afraid, Callum, that is that

Callum 18:12

That is right

Jame 18:13

That is rat. Oh, that was so good. That's a much better pun at the end than the one you had at the start. Oof

Callum 18:20

Well

Jame 18:21

Still thinking of something? Quit while you're ahead, buddy