Sara Dong: Hi, everyone.
Welcome to Febrile, a cultured podcast about all things infectious disease.
We use consult questions to dive into ID clinical reasoning, diagnostics,
and antimicrobial management.
I'm Sara Dong, your host and a MedPeds ID doc.
I am super pumped to bring you another international episode today.
We are joined by a team from Australia.
First up, I'll introduce our host, Dr.
Genevieve Martin.
She is undertaking her training in ID at the Royal Darwin Hospital in
the Northern Territory, Australia.
She completed her PhD in the immunology of early HIV infection
and HIV cure approaches at the University of Oxford in 2018.
Genevieve Martin: Hi, my name is Genevieve Martin.
I'm an infectious diseases registrar at the Royal Darwin hospital, and
I'm really glad to be here today.
Sara Dong: We have two additional consultants today.
Dr.
Catherine Marshall is the co director of the Department of
Infectious Diseases and is an ID physician at Royal Darwin Hospital.
Catherine Marshall: I'm Dr.
Catherine Marshall, the co director of Infectious Diseases at Royal Darwin
Hospital, and I'm thrilled to be here.
Thanks.
Sara Dong: And we are also joined by Professor Bart Currie, who is an ID
physician at Royal Darwin and also works in the Menzies School of Health Research.
Bart Currie: Good morning or good evening, I'm Bart Currie, an infectious
disease physician here at Royal Darwin Hospital and also working at the
Menzies School of Health Research.
Thank you.
Sara Dong: Great.
I'm so excited you guys are here.
Before we jump in, we always ask one quick question.
As everyone's favorite cultured podcast, I'd love to hear you share a little
piece of culture, you know, something that brings you joy outside of work.
Genevieve Martin: It's early days to call it something good, but I've just
started reading The Bee Sting by Paul Murray, and I think it's going to be good.
Catherine Marshall: So one of my favourite things to do in Darwin each year is to
visit the National Aboriginal and Torres Strait Islander Art Awards that are shown
at the Museum and Art Gallery of the Northern Territory, and there's a fabulous
array of art from all over the country.
Genevieve Martin: Oh, it's great.
I went a couple of weeks ago.
Bart Currie: My naturalist colleagues here up in the tropical north of
Australia have told me that the snakes have been very unusual in their behavior
over the last three or four months.
They've been on the move and they've also been, the newborns have been
hatching or the eggs have been hatching and the liveborns have been coming,
coming out earlier than normal.
We've had a substantial number of bites from snakes in the last few months,
more than I think we've ever seen.
Genevieve Martin: In addition to being an infectious disease
physician, Bart Currie is also our snake bite management expert up here.
Bart Currie: I guess it is mixing work with pleasure.
Sara Dong: Well, thank you guys so much for sharing.
Genevieve, well, I'm looking forward to hearing about your consult.
Genevieve Martin: Okay, perfect.
This scenario is, you receive a call in late January, the wet season,
from the emergency department that a 42 year old male has arrived,
having been flown in from a remote community in the Northern Territory.
The patient's being brought into his local clinic by family members.
History reveals two to three days of cough and subjective fevers.
The observations taken in the remote clinic showed a fever of 38.
9 degrees Celsius, tachycardia at 108 beats per minute, a blood
pressure of 109/62, and a respiratory rate of 28, meeting SIRS criteria.
One set of blood cultures was taken and the patient was given a stat dose
of ceftriaxone and gentamicin, along with crystalloid fluid resuscitation.
Having now arrived in the ED, he remains tachypneic and tachycardic
with a GCS of 14, scored for confusion.
He is now requiring 2 litres of oxygen to maintain oxygen
saturations greater than 94%.
Initial blood work is taken and is pending.
At this point, what further information would you like, and what
investigations would you suggest that the emergency department request?
Catherine Marshall: Thanks Genevieve.
So I guess I would be concerned that this patient has bacterial sepsis due
to a lower respiratory tract infection and I would want to know what their
comorbidities were and whether they were a smoker or a heavy drinker of alcohol.
We know that excessive alcohol consumption is a risk factor for
both melioidosis and community acquired Acinetobacter infection.
I'd also want to know whether they've had any water or animal exposures that
would put them at risk of infections such as leptospirosis or Q fever,
and I'd want to know whether they've had any recent skin infections or
abscesses that may indicate a risk for disseminated Staph aureus infection.
I'd recommend that the emergency department undertook further blood
cultures, sputum and urine cultures, and a chest x ray in the first instance.
In our emergency department, they'd also do a gene expert
PCR for COVID/Influenza/RSV.
I'd also suggest sending serology for melioidosis, and we also do a,
or recommend a throat and rectal swab that is then incubated in a
selective media called Ashdown's Media, looking specifically for melioidosis.
Given the confusion in this patient, I think that they're going to likely need
imaging of the brain with at least a CT scan and probably a lumbar puncture
to exclude a meningoencephalitis after they're stable from an initial
resuscitation perspective, and I guess although less likely, I may also
suggest sending a blood and urine for say, leptospirosis PCR, and serology.
Genevieve Martin: Well, we have some of that information.
So in terms of past medical history, the emergency department staff have been
unable to identify any relevant past medical history, and they've confirmed
that the, the patient, uh, does not, has very little contact with his local clinic.
With regards to alcohol use, they've spoken with family who've reported
that he does not drink any alcohol and is not a smoker, but that he
does spend a lot of time fishing in the rivers around the community.
Initial blood work is now back, which shows a raised white cell count at 23.
2 with a predominant neutrophilia and a C reactive protein at 391 mg per litre.
His creatinine is elevated at 156 giving a GFR of 46 with a lactate of 3.
2, ketones 2.
4 and sodium 129.
He has a normal bilirubin of 7 with liver enzyme derangement
that's predominantly cholestatic.
The patient's noted to have a macrocytic anemia with a hemoglobin
of 110 and an MCV of 105.
Chest X ray shows bilateral consolidation and neuroimaging is still pending.
Despite a further 2 litres of fluid resuscitation, he remains hypotensive
and is being transferred to the intensive care unit for vasopressor support.
At this stage, what empiric antimicrobials would you suggest and why?
Catherine Marshall: So I would initially recommend treatment for severe community
acquired pneumonia, which according to our local guidelines in the wet season
would include a combination of meropenem that covers the usual well known organisms
that cause community acquired pneumonia such as streptococcal pneumoniae.
But we'll also cover Burkholderia pseudomallei, the agent causing
melioidosis, and community acquired Acinetobacter baumannii, which also
can be a cause of community acquired pneumonia in our tropical region.
And that would also provide cover for leptospirosis.
I'd also recommend vancomycin to cover for MRSA, and azithromycin
to provide some atypical cover, particularly thinking of Legionella.
Genevieve Martin: Okay, thank you for that.
So the patient's been admitted to the intensive care unit, and on your
advice has been commenced on meropenem, vancomycin, and azithromycin, but has
an ongoing noradrenaline requirement.
He's requiring oxygen via nasal prongs, but no additional respiratory
supports, and has been commenced on an insulin infusion to assist in
management of hyperglycemia and ketosis.
An HbA1c has just returned at 10.
2%, consistent with undiagnosed diabetes mellitus.
The intensive care team have received a phone call to say that a blood culture
taken in community is growing in atypical motile gram negative bacillus, which
they suspect may be a contaminant.
The two further sets taken in the emergency department
remain negative at this stage.
Based on this information, Burkholderia pseudomallei is strongly suspected
to be the causative organism.
I'm wondering, Bart, if you could tell us a little bit more about the
additional diagnostic tests that might be available at this stage
to help us confirm the diagnosis.
Bart Currie: Yes, thanks Genevieve.
So, melioidosis is always diagnosed still by having a culture.
That's the only thing that will fulfill the definition of confirmed
melioidosis is a laboratory culture for Burkholderia pseudomallei.
The organism was thought by the laboratory initially, not our hospital
laboratory, but the external laboratory, to maybe be a contaminant, which is
not unusual for places where they may not see this organism so commonly.
So, the thing about the organism is that it's a motile gram negative rod,
it's oxidase positive, non lactose fermenting, and it has bipolar staining.
In laboratories which do not have a lot of resources, there's a 3 disk
diffusion test that can be used, which is using gentamicin, to which
Burkholderia pseudomallei is resistant, and also colistin disc, and also an
amoxicillin cladolanic acid disc.
And Burkholderia pseudomallei is sensitive to amoxi-clav, but resistant
to gentamicin and colistin, so that three disc test has been very useful
to make people think that this is B.
pseudomallei.
Then to confirm that the organism is B.
pseudomallei, there have traditionally been various biochemical profiles,
but there are also automated tests such as Vitek and MaldiTOF.
The problem with Vitek and MaldiTOF, and there have been a number of publications
over the years, is that historically, they would sometimes misidentify B.
pseudomallei as another Burkholderia species or indeed some other organisms,
but more recently, with improved database profiles, such as an increased number
of mass spectra profiles in the MALDI TOF, the specificity of these automated
detection systems have been much improved, so that the final confirmation
can be made on those systems usually.
However, in addition to that, there is also the ability to do a PCR on a culture
and also there is a non commercial lateral flow assay that can be used.
Genevieve Martin: Okay.
Fantastic.
That's really helpful.
So to return briefly to the case, based on some advice provided by our team, some
further investigations are performed.
A CT of the chest and abdomen and pelvis is performed revealing a dense right
sided consolidation and left middle zone changes without any cavitation
or associated pleural effusion.
There is evidence of multiple splenic hypodensities reported to
favour infection or infarction.
This CT has also identified a very large 24 by 18 millimetre prosthetic abscess.
Urology have been referred to consider drainage of this.
And the urine sent on admission has greater than 100 leukocytes on
microscopy and is now growing a motile gram negative organism with bipolar
staining, which the lab has confirmed is morphologically consistent with
Burkholderia pseudomallei, and a PCR of a throat rectal swab cultured in Ashdown's
media is also positive for this organism.
Together, these investigations confirm a diagnosis of melioidosis.
What is your approach to the initial management of this infection?
Catherine Marshall: Thanks Genevieve.
So I think we'd be comfortable now that this patient, as you mentioned,
has disseminated melioidosis with involvement with pneumonia, likely
splenic abscesses and a prostatic abscess.
So, our initial management would include appropriate antimicrobial therapy,
which would be intravenous in the first instance with either meropenem
or ceftazidime, and we usually prefer meropenem in the intensive care setting.
Given that there's deep abscesses, particularly in the prostate, we
would also add a second agent, so cotrimoxazole, as, you know, additional
agent to improve penetration, particularly within the prostate.
The other critical component of initial management is source control, so in
this case we would recommend drainage of the prostatic abscess, which might
be done either by the urologist or is sometimes done by our radiology colleagues
transrectally using ultrasound guidance.
There would also need to be assessment of the splenic abscess about whether
that would need further drainage, but often we can manage those
conservatively with antibiotics alone.
Genevieve Martin: On day four of ICU admission, the patient's being
weaned off inotropic support with improving inflammatory markers.
Atraumatic swelling of the left knee is noted and a diagnostic aspirate
performed at the bedside reveals a synovial white cell count of 38, 000
cells with no organisms or crystals seen.
Burkholderia pseudomallei PCR and a lateral flow assay for the
Burkholderia pseudomallei antigen on synovial fluid is positive.
How frequently is musculoskeletal involvement encountered and does
this change your management?
Bart Currie: Thanks Genevieve.
So just taking a step back, this, this patient represents the severe
end of the spectrum of melioidiosis.
So it's a person who has severe sepsis, they're bacteremic, and the organism is
primarily probably caused a pneumonia initially and then seeded to prostate,
spleen, and now, as evident, to a joint.
Overall, over half of the patients who present with melioidiosis are bacteremic,
and the primary presentation in around half of the patients is a pneumonia,
with subsequent seeding in some of them.
Overall, 21 percent of the patients do present like this with septic shock
requiring intensive care management.
Then the lesser end of the spectrum of presentation, which is not this patient,
are people who may have a primary skin lesion without systemic sepsis
or people presenting primarily with a genitourinary infection where the prostate
abscess may be the initial presentation rather than having seeded there, with
pneumonia being the primary presentation.
So overall, in answer to the question, septic arthritis is very
rare as a primary presentation, around about 3 percent of our cases.
And osteomyelitis, even less common, 1 percent of our primary cases, but
within the three weeks following initial presentation, seeding to bone
and joint is certainly well recognized.
So an additional 3 percent of patients will seed to joints,
such as in this patient, 3 percent seed to joint with osteomyelitis.
And we also have seeding to muscles, so muscle abscesses in sometimes
multiple different muscles will present in 3 percent of patients, subsequent
to their initial presentation.
So that's the spectrum of melioidiosis.
And if the way it changes management is, is that, as Katherine mentioned,
abscesses often need to be drained and certainly joints need to be, initially
after the aspiration, usually washed out.
And it's not uncommon for joints to need to have a second washout.
And so what we do is that we reset the clock for the intravenous
antibiotics every time we do an aspirate, or a washout, or a drainage
of an abscess, provided that it is culture positive, which it usually is.
So that then resets our clock for the antibiotic duration for
the intravenous antibiotics.
Genevieve Martin: And I guess that leads into the next question.
Once appropriate source control has been achieved, and we're happy that that's
the case, the duration of antimicrobials used for melioidiosis is much longer
than other gram negative infections.
How long do you need to treat for, and what's the approach to this?
Catherine Marshall: As alluded by Bart, the treatment of melioidiosis
involves an intensive intravenous phase, which is followed then by an oral
eradication phase, and the duration of the intensive phase varies depending on
the source and extent of the infection.
For a simple limited bacteremia or limited mild pneumonia, that may be you
know, two weeks of intravenous therapy.
But if there is disseminated disease, say, for example, with central
nervous system involvement, this may be as long as eight weeks.
And as Bart mentioned before, time is taken from either the date of the
last positive culture or the time that source control has been achieved with
either, you know, drainage of an abscess.
In this case, where there are deep collections and septic arthritis, the
patient would require a minimum of four weeks of intravenous therapy from
the time of source control, but if it subsequently discovered that they had
osteomyelitis associated with their septic arthritis, then that would
need to be extended to six weeks.
Following the intravenous phase, there is ongoing eradication therapy, which
usually involves oral cotrimoxazole for a minimum of three months.
That would be extended out to six months if there were CNS
involvement or osteomyelitis.
If cotrimoxazole is not tolerated, then doxycycline is
used as a second line therapy.
Genevieve Martin: This patient is improving and nearing discharge from
our hospital in the home service, having completed six weeks of
intravenous therapy with ceftazamine.
They've been established on trimethoprim-sulfamethoxazole at a
high dose of 320 / 1600 milligrams orally twice a day with additional
folic acid supplementation.
They're tolerating this regimen well with no significant adverse reactions.
They ask you why they became sick with this infection in the first place.
How do you counsel them about risk factors and prevention of infection?
Bart Currie: I think that taking a step back in, in relation to prevention
of melioidiosis, which would also be the information passed on to this
patient because people can get a second infection with melioidiosis.
What we have recognized over time with our studies here in Darwin is that
melioidiosis is very much considered as an opportunistic infection, so healthy people
rarely get very sick from melioidiosis.
And indeed, only 16 percent of our cases are people who have
identified clinical risk factors.
So that our emphasis for public health is on the people who have the risk
factors and for them to avoid exposure to the organism during the wet season
when 85 percent of our cases happen.
Our wet season here is from basically November through to the end of April.
And it's during that time that the majority of our cases happen when
people have an exposure to wet season, soil, mud, or surface water.
What are those risk factors?
Well, up to 50 percent of our cases are people living with diabetes.
Sometimes, diabetes has not been diagnosed until the episode of meliodosis.
Hazardous alcohol use is unfortunately common in our part of the world here
as a risk factor for meliodosis.
And then people with chronic lung disease, chronic kidney disease, and then
increasingly we're seeing our patients who have malignancies and particularly
after they go on immunosuppression and most notably corticosteroid therapy, they
are people who are really magnets for melioidiosis during the wet season and so
for those people in the high risk groups.
We actually recommend that when the wind and rains come, that they stay
indoors during periods of heavy wind and rain because while the majority
of infections are thought to be percutaneous exposure through either
cuts or trauma, there's clearly a shift to inhalational melioidiosis when there
is actually windy and rainy events and so we recommend people with those risk
factors stay indoors and if they have to go outside they even wear a mask.
One of the things we've found most recently, in the last few years,
is that people using high pressure hoses to clean off pavements or to
clean their cars have been getting infected through aerosolization.
So these are all the things that can put people at risk of melioidiosis.
And the final point is that children are not at risk
usually of getting melioidiosis.
We of course will have the occasional case with a single skin sore or an
immunosuppressed child unfortunately may well get melioidiosis and become sick.
But overall, less than 4 percent of our patients are children aged under 15 years.
Genevieve Martin: I guess we've talked a little bit about melioid
up here in the top end, Burkholderia pseudomallei is found in the soil
in tropical and subtropical regions, including the top end of Australia
where we work in endemic areas.
The incidence of melioidiosis, as you've mentioned, has a
strong link with weather events.
What do we know about the environmental niche of Burkholderia
pseudomallei, and is this linked to changing regions of endemicity?
Bart Currie: That's a fascinating area, and there's a lot of our colleagues
around the world and including in the Americas, working on this.
Issue of what is or what are the environmental niches for
Burkholderia pseudomallei.
We know that it's been endemic for a long period of time in much of the
tropics and subtropics and it's only been when people have brought laboratory
resources to regions such as in parts of Africa and indeed in South America and
the Caribbean that people have started to diagnose cases of melioidiosis.
The organism is natural to many of these tropical environments, and
it has a selective advantage over other environmental organisms, in
particularly soils which are nutrient deplete, so poor soils with lower
pH, where the organism is able to survive and outcompete other organisms.
There's a natural role in the environment.
Its hypothesized to be in symbiosis with the rhizosphere of various
plants, or the root systems, where this organism, Burkholderia pseudomallei,
is able, through its vast array of virulence factors, to provide a
biodefense for those plants against invading bacteria, fungi, and protozoa.
The issue for the Americas is fascinating because, while melioidiosis has
been endemic for a long time in many parts of the world, in the United
States, it is now being found for the first time to be actually endemic
in the Gulf State of Mississippi.
And this was published in the New England Journal of Medicine just last
year, following three cases in the years between 2020 and 2023 from a particular
county on the Gulf Coast of Mississippi.
So this is an emerging issue.
And our colleagues at CDC in the U.
S.
are working hard with the state health authorities in Mississippi
to find out how it got there and how widespread it might be.
Is it in other Gulf states in the United States?
What the genotyping has shown of those bacteria is that they
are a Western Hemisphere strain.
So it has potentially moved from the Americas through the Caribbean and then
from Southern America and Caribbean into the Southern United States.
Our colleagues at the CDC are experts at advising people on that and they have
resources available for both diagnosis and advice on therapy as well if there
should be an emerging case somewhere.
And remember that also that of those 12 cases, the majority have
been imported cases through various products brought into the U.
S.
or returned travellers.
There was a case in 2019 related to an aquarium that had fish which
were imported from Southeast Asia.
The, aquarium was positive for Burkholderia pseudomallei, the
water was, and that linked, uh, was identical on genotyping to
the isolate from the patient.
You might be aware that there was the tragedy of the four cases in the U.
S.
which was from imported aromatherapy spray from India.
Four cases, two fatal, and one of those fatalities was in a child
who was co infected with COVID.
That was in four different states, and it was an aromatherapy product
imported, which was contaminated with B.
pseudomallei.
And again, the genotyping, we've linked the isotopes from the
patients to that aromatherapy spray.
So these are the sort of scenarios, so imported cases certainly happen, return
travellers have melioid and now you have it endemic in the US, so watch this space.
Genevieve Martin: Okay, fantastic.
I feel like I'm always learning so much listening to you talk about melioid.
Before we wrap up, are there any other pearls of wisdom you
have to share with the audience?
Bart Currie: I guess there's a number of things of interest and importance.
One is our lack of understanding still of how quickly it is
spreading around the world.
And so in other words, the unmasking of long term endemicity versus, uh,
spread such as I mentioned into the Southern United States, and then what
will happen over the next few decades.
There is modeling suggesting that with global warming, the organism will continue
to proliferate potentially more rapidly and in a more diverse geographic range
because of the nature of the weather that we're facing and the climate
future that we're facing in the world.
The other thing is, is that as an opportunistic pathogen, which particularly
is an issue for people living with diabetes, the incredible increase in
diabetes worldwide, particularly in lower income countries and such as in Southeast
Asia, parts of Southeast Asia, and in the Americas as well, and also in Africa.
It means that there's going to be an enormous number of people
who are susceptible to getting unwell should they become infected.
And I guess the final point is that the positive side of things is that
there's actually a vaccine on the horizon, and there are three vaccines
that are currently in active study, and it's hoped that there will be, in
the next 12 to 18 months, the first ever in human trial of some of the
first of these vaccines for mellidosis.
Genevieve Martin: Okay, fantastic.
Sara Dong: Thank you so much to Genevieve, Catherine, and
Bart for joining Febrile today.
This was a really awesome episode.
Don't forget to check out the website, febrilepodcast.
com, where you'll find the Consult Notes, which are written complements
of the show with links to references, our library of ID infographics,
and a link to our merch store.
Febrile is produced with the support of the ID Society of America.
Audio editing and mixing is provided by Bentley Brown.
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Thanks for listening, stay safe, and I'll see you next time.