94: Of Microbes and Mud

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.

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?

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.

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?

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.

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.

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.

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?

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.

How frequently is musculoskeletal involvement encountered and does this change your management?

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.

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.

How do you counsel them about risk factors and prevention of infection?

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.

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.

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.

Please reach out if you have any questions, suggestions for future shows, or want to be more involved with Febrile. Thanks for listening, stay safe, and I'll see you next time.