Febrile #94 – Of Microbes and Mud

March 4, 2024

Summary

Drs. Genevieve Martin, Catherine Marshall, and Bart Currie from the Royal Darwin Hospital share their approach to Burkholderia pseudomallei aka melioidosis!

Credits

Hosts: Genevieve Martin, Sara Dong

Guest Discussants: Catherine Marshall, Bart Currie

Writing: Genevieve Martin

Content Editing, Infographics, Cover Art: Sara Dong

Audio Editing/Mixing: Bentley Brown

Produced by Sara Dong with support from the Infectious Diseases Society of America (IDSA)

Our Guests

Check out this wonderful team photo and Genevieve’s delightful melioidosis plate biscuits/cookies !

Dr Catherine Marshall

Dr Catherine Marshall is the Co-Director of the Department of Infectious Diseases and an ID physician at Royal Darwin Hospital. She completed her ID training at the Alfred Hospital in Melbourne, and she also completed an MPH.

Dr Genevieve Martin

Dr Genevieve Martin is an Infectious Diseases Advanced Trainee 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. She is passionate about understanding the interactions between pathogens and the immune system and aspirates to combine clinical work as an ID physician with her research

Professor Bart Currie

Professor Bart Currie is a senior staff specialist ID physician at the Royal Darwin Hospital, where he was the Director of ID until 2019. He was initially head of the Menzie Clinical Division and the Interim Director of the Menzies School of Health Research, and he now leads the Tropical and Emerging Infectious Diseases team within the Global and Tropical Health Division. His collaborations with clinical and scientific colleagues have resulted in hundreds of peer reviewed publications.

Culture

Genevieve just started reading “The Bee Sting” by Paul Murray
Catherine shared how she loves to visit the Darwin National Aboriginal & Torres Strait Islander Art Awards at the Museum and Art Gallery of Northern Territory. Check out some archives at this link
Bart shared that snakes have been unusual in their behavior in last few months! More on the move and newborns have been hatching, so there have been several snakebites!

Consult Notes

Case Summary

42 yo male presents with cough and fevers from a remote community in the Northern Territory Australia during the wet season. He was found to have melioidosis

Key Points

Key References

Meumann EM, Limmathurotsakul D, Dunachie SJ, Wiersinga WJ, Currie BJ. Burkholderia pseudomallei and melioidosis. Nat Rev Microbiol. 2024;22(3):155-169. doi:10.1038/s41579-023-00972-5

Meumann EM, Cheng AC, Ward L, Currie BJ. Clinical features and epidemiology of melioidosis pneumonia: results from a 21-year study and review of the literature. Clin Infect Dis. 2012;54(3):362-369. doi:10.1093/cid/cir808

Currie BJ, Mayo M, Ward LM, et al. The Darwin Prospective Melioidosis Study: a 30-year prospective, observational investigation. Lancet Infect Dis. 2021;21(12):1737-1746. doi:10.1016/S1473-3099(21)00022-0

Sullivan RP, Marshall CS, Anstey NM, Ward L, Currie BJ. 2020 Review and revision of the 2015 Darwin melioidosis treatment guideline; paradigm drift not shift. PLoS Negl Trop Dis. 2020;14(9):e0008659. Published 2020 Sep 28. doi:10.1371/journal.pntd.0008659

Burkholderia pseudomallei or melioidosis epidemiology

An infection caused by the facultative intracellular Gram negative bacteria B.pseudomallei
Historically endemic areas include Southeast Asia, northern Australia, South Asia, and China → with the majority of cases from Thailand, Malaysia, SIngapore, and northern Australia
Cases have been described in other regions though, and the global distribution remains unclear
- - Most of these will be cases acquired by visitors to endemic areas
  - Sporadic human and animal cases that are no travel related though have been reported, making the boundaries less clear
  - See the section on the US later for more details…
Transmission can occur via:
- - Percutaneous inoculation → the predominant mode of transmission during exposure to wet season soils or contaminated water
    - - Cases of pneumonia after presumptive inoculation of skin injuries are well documented → suggesting infection reaches lungs via hematogenous route
  - Inhalation
  - Aspiration
  - Occasional ingestion
Risk factors for melioidosis
- - In endemic areas, the environmental exposure to soil and water is an important risk. Activities such as gardening or landscaping and the season are important as well. Severe weather events like monsoons can be associated with local clusters of infection as well
  - Important comorbidities include: diabetes mellitus, alcohol use, chronic kidney disease, chronic lung disease
Incubation period can range from 1-21 days but mean is about 5-9 days → this is likely influenced by inoculating dose, mode of transmission, and host risk factors
Additional references (also see first section!):

Melioidosis in the USA

As Bart discussed, cases of melioidosis in the US are rare and typically travel associated, but there have recently been several non-travel-related cases and evidence supporting that B.pseudomallei is potentially endemic in the southern US
- - B.pseudomallei has been identified in environmental samples of soil and water from the Mississippi Gulf Coast region, which were genetically linked to isolates cultured from 3 unrelated patients who presented with melioidosis. Petras JK, Elrod MG, Ty MC, et al. Locally Acquired Melioidosis Linked to Environment – Mississippi, 2020-2023. N Engl J Med. 2023;389(25):2355-2362. doi:10.1056/NEJMoa2306448
  - There also has been another non-travel-related case in Texas: Cossaboom CM, Marinova-Petkova A, Strysko J, et al. Melioidosis in a Resident of Texas with No Recent Travel History, United States. Emerg Infect Dis. 2020;26(6):1295-1299. doi:10.3201/eid2606.190975
You may also remember the cases in a multistate outbreak recently identified from imported aromatherapy spray
- - Gee JE, Bower WA, Kunkel A, et al. Multistate Outbreak of Melioidosis Associated with Imported Aromatherapy Spray. N Engl J Med. 2022;386(9):861-868. doi:10.1056/NEJMoa2116130

Clinical features of melioidosis

Infections may be asymptomatic or subclinical in most cases, and severe disease typically occurs in those with certain comorbidities
Most cases occur in adults. When cases in children do occurs, they tend to be less severe
- - McLeod C, Morris PS, Bauert PA, et al. Clinical presentation and medical management of melioidosis in children: a 24-year prospective study in the Northern Territory of Australia and review of the literature. Clin Infect Dis. 2015;60(1):21-26. doi:10.1093/cid/ciu733
Acute infection is typically pneumonia, which accounted for over half of cases in the Northern Territory of Australia
- - Other sites of infection include skin and soft tissue, genitourinary tract, and visceral abscesses (often noted in spleen, kidney, prostate)
  - Bacteremic spread of the organisms can result in disease at almost any body site
Chronic infection can occur with majority of these presenting with chronic pulmonary symptoms that may mimic TB or with a non-healing skin ulcer
Latent infection with reactivation is possible, similar to TB

Diagnosis of melioidosis

In endemic regions, melioidosis is routinely considered part of the differential diagnosis of pneumonia, ulcerated skin lesions, undifferentiated sepsis, prostatic abscess – similar to our case episode
Outside of endemic areas, consider if individual present with syndrome, history of travel to an endemic area, and travel or residence to areas where cases are being increasingly reported
When melioidosis is suspected, collect specimens from appropriate sites including: blood, sputum/respiratory, urine, throat swab, rectal swab, swab from any ulcer or skin lesion, pus/fluid from drainable abscesses, CSF if individual with encephalitis or meningitis (although CSF yield is low)
- - Likelihood of diagnosis is increased if multiple clinical samples are sent
  - As discussed in the episode, in the Northern Territory of Australia (a hyperendemic region), all cultures from blood, sputum, urine, and drainage are collected during wet season when cases peak and are processed for B.pseudomallei detection
B.pseudomallei grows in standard blood cultures
In cultures from non sterile sites, it can be overgrown by normal flora, so selective media can be used → our guests discussed Ashdown agar, which contains gentamicin, or Ashdown liquid transplant broth, which contains colistin
B.pseudomallei is oxidase-positive, non-lactose-fermenting, Gram-negative bacillus → so once the organism grows, identification can be made with screening with Gram stain, oxidase reaction, typical growth characteristics, and resistance to certain antibiotics (as Bart discussed)
- - Dance DA, Wuthiekanun V, Naigowit P, White NJ. Identification of Pseudomonas pseudomallei in clinical practice: use of simple screening tests and API 20NE. J Clin Pathol. 1989;42(6):645-648. doi:10.1136/jcp.42.6.645
Serology is generally not useful
Other antigen and DNA detection techniques exist but are not always commercially available

Treatment of melioidosis

B.pseudomallei is intrinsically resistant to penicillin, ampicillin, first and second generation cephalosporins, gentamicin, tobramycin, and streptomycin
The main antimicrobial options (depending on phase of treatment) include:
- - Beta-lactams (ceftazidime, certain beta-lactam-beta-lactamase-inhibitors) and carbapenems
  - TMP-SMX
  - Doxycycline
Therapy generally begins with an initial intensive therapy phase
- - The goal is to prevent mortality from severe illness, and this typically includes at least 2 wks of IV antibiotic therapy (although this may be 4-8 wks in some cases)
  - Generally for critically ill patients, experts would use meropenem as initial therapy. There is observational data to suggest meropenem may offer mortality benefit
    - - Stephens DP, Thomas JH, Ward LM, Currie BJ. Melioidosis Causing Critical Illness: A Review of 24 Years of Experience From the Royal Darwin Hospital ICU. Crit Care Med. 2016;44(8):1500-1505. doi:10.1097/CCM.0000000000001668
      - Cheng AC, Fisher DA, Anstey NM, Stephens DP, Jacups SP, Currie BJ. Outcomes of patients with melioidosis treated with meropenem. Antimicrob Agents Chemother. 2004;48(5):1763-1765. doi:10.1128/AAC.48.5.1763-1765.2004
  - If there is concern for CNS involvement, experts use meropenem at higher dosing (40 mg/kg up to 2g IV every 8 hrs)
  - In non-critically ill patients without CNS infection, could consider use of ceftazidime for initial therapy. Could also consider transition of meropenem to ceftazidime following clinical improvement for antibiotic stewardship
  - In some cases, adjunctive addition of TMP-SMX may be used as well (such as those with non-pulmonary focal infections → rationale is added tissue penetration and intracellular activity of TMP-SMX). The data though is limited on this approach
    - - Chierakul W, Anunnatsiri S, Short JM, et al. Two randomized controlled trials of ceftazidime alone versus ceftazidime in combination with trimethoprim-sulfamethoxazole for the treatment of severe melioidosis. Clin Infect Dis. 2005;41(8):1105-1113. doi:10.1086/444456
      - Chierakul W, Anunnatsiri S, Chaowagul W, Peacock SJ, Chetchotisakd P, Day NP. Addition of trimethoprim-sulfamethoxazole to ceftazidime during parenteral treatment of melioidosis is not associated with a long-term outcome benefit. Clin Infect Dis. 2007;45(4):521-523. doi:10.1086/520010
This intensive phase is followed by oral antibiotic eradication therapy
- - Considered necessary to prevent relapse
    - - Chaowagul W, Suputtamongkol Y, Dance DA, Rajchanuvong A, Pattara-arechachai J, White NJ. Relapse in melioidosis: incidence and risk factors. J Infect Dis. 1993;168(5):1181-1185.
      - Limmathurotsakul D, Chaowagul W, Chierakul W, et al. Risk factors for recurrent melioidosis in northeast Thailand. Clin Infect Dis. 2006;43(8):979-986. doi:10.1086/507632
  - Experts typically suggest PO TMP-SMX although doxycycline is an alternative agent
  - The optimal duration of this phase is unknown, although most experts suggest a minimum of 3 months
    - - Can be extended in 6 months in those with osteomyelitis or neurologic disease
      - In those with vascular involvement / mycotic aneurysms, may consider even longer duration or lifelong therapy
Other critical parts of management include
- - Abscess drainage as appropriate, especially with prostatic abscess
  - Supportive care
  - Consideration of recombinant G-CSF for patients with septic shock

Prevention of melioidosis

Bart discussed counseling individuals with risk factors who live in endemic areas to avoid skin exposures to soil and surface water during the wet season, including staying inside during severe weather that may increase aerosolization of B.pseudomallei
It is recommended that patients with cystic fibrosis should avoid travel to melioidosis endemic regions during wet season

Episode Art & Infographics

Infographics

Find all the Febrile infographics here!

Goal

Listeners will be able to discuss the diagnosis and management of melioidosis

Learning Objectives

After listening to this episode, listeners will be able to:

Identify hyperendemic areas for Burkholderia pseudomallei
Describe the common clinical syndromes associated with melioidosis
Discuss management of severe melioidosis

Disclosures

Our guests as well as Febrile podcast and hosts report no relevant financial disclosures

Citation

Martin, G., Marshall, C., Currie, B., Dong, S. “#94: Of Microbes and Mud”. Febrile: A Cultured Podcast. https://player.captivate.fm/episode/4cf87987-c1ca-421d-a6f3-c8b974d26759

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