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Use of Comparative Genomics To Resolve an Unusual Case of Aminoglycoside Susceptibility in the Melioidosis Pathogen Burkholderia pseudomallei in Bangladesh

Kaestli M, Farook S, Jilani MSA, Anwar S, Siddiqui TA, Mayo M, et al.

Am J Trop Med Hyg, 2024 Sep 03.
PMID: 39226893 DOI: 10.4269/ajtmh.24-0144

Melioidosis is an emerging tropical infectious disease with a rising global burden caused by the environmental bacterium Burkholderia pseudomallei. It is endemic in Southeast and South Asia, including Bangladesh. A rare aminoglycoside-susceptible B. pseudomallei isolate (Y2019) has recently been reported from a melioidosis patient in Dhaka, Bangladesh. To understand the geographical origins of Y2019, we subjected it and 10 other isolates from Bangladesh to whole-genome sequencing. In a phylogenetic tree with a global set of B. pseudomallei genomes, most Bangladeshi genomes clustered tightly within the Asian clade. In contrast, Y2019 was closely related to ST881 isolates from Sarawak, Malaysian Borneo, a gentamicin-sensitive sequence type, suggesting infection in Borneo. Y2019 also contained the same gentamicin sensitivity conferring nonsynonymous mutation in the drug efflux pump encoding the amrB gene. In the absence of a full travel history, whole-genome sequencing and bioinformatics tools have revealed the likely origin of this rare isolate.
Fulltext Exploring Cefiderocol Resistance Mechanisms in Burkholderia pseudomallei

Hall CM, Somprasong N, Hagen JP, Nottingham R, Sahl JW, Webb JR, et al.

Antimicrob Agents Chemother, 2023 Jun 15;67(6):e0017123.
PMID: 37133377 DOI: 10.1128/aac.00171-23

Cefiderocol is a siderophore cephalosporin designed mainly for treatment of infections caused by β-lactam and multidrug-resistant Gram-negative bacteria. Burkholderia pseudomallei clinical isolates are usually highly cefiderocol susceptible, with in vitro resistance found in a few isolates. Resistance in clinical B. pseudomallei isolates from Australia is caused by a hitherto uncharacterized mechanism. We show that, like in other Gram-negatives, the PiuA outer membrane receptor plays a major role in cefiderocol nonsusceptibility in isolates from Malaysia.
Fulltext Reliability of automated biochemical identification of Burkholderia pseudomallei is regionally dependent

Podin Y, Kaestli M, McMahon N, Hennessy J, Ngian HU, Wong JS, et al.

J Clin Microbiol, 2013 Sep;51(9):3076-8.
PMID: 23784129 DOI: 10.1128/JCM.01290-13

Misidentifications of Burkholderia pseudomallei as Burkholderia cepacia by Vitek 2 have occurred. Multidimensional scaling ordination of biochemical profiles of 217 Malaysian and Australian B. pseudomallei isolates found clustering of misidentified B. pseudomallei isolates from Malaysian Borneo. Specificity of B. pseudomallei identification in Vitek 2 and potentially other automated identification systems is regionally dependent.
Fulltext Molecular investigations of a locally acquired case of melioidosis in Southern AZ, USA

Engelthaler DM, Bowers J, Schupp JA, Pearson T, Ginther J, Hornstra HM, et al.

PLoS Negl Trop Dis, 2011 Oct;5(10):e1347.
PMID: 22028940 DOI: 10.1371/journal.pntd.0001347

Melioidosis is caused by Burkholderia pseudomallei, a Gram-negative bacillus, primarily found in soils in Southeast Asia and northern Australia. A recent case of melioidosis in non-endemic Arizona was determined to be the result of locally acquired infection, as the patient had no travel history to endemic regions and no previous history of disease. Diagnosis of the case was confirmed through multiple microbiologic and molecular techniques. To enhance the epidemiological analysis, we conducted several molecular genotyping procedures, including multi-locus sequence typing, SNP-profiling, and whole genome sequence typing. Each technique has different molecular epidemiologic advantages, all of which provided evidence that the infecting strain was most similar to those found in Southeast Asia, possibly originating in, or around, Malaysia. Advancements in new typing technologies provide genotyping resolution not previously available to public health investigators, allowing for more accurate source identification.
Fulltext Burkholderia pseudomallei isolates from Sarawak, Malaysian Borneo, are predominantly susceptible to aminoglycosides and macrolides

Podin Y, Sarovich DS, Price EP, Kaestli M, Mayo M, Hii K, et al.

Antimicrob Agents Chemother, 2014;58(1):162-6.
PMID: 24145517 DOI: 10.1128/AAC.01842-13

Melioidosis is a potentially fatal disease caused by the saprophytic bacterium Burkholderia pseudomallei. Resistance to gentamicin is generally a hallmark of B. pseudomallei, and gentamicin is a selective agent in media used for diagnosis of melioidosis. In this study, we determined the prevalence and mechanism of gentamicin susceptibility found in B. pseudomallei isolates from Sarawak, Malaysian Borneo. We performed multilocus sequence typing and antibiotic susceptibility testing on 44 B. pseudomallei clinical isolates from melioidosis patients in Sarawak district hospitals. Whole-genome sequencing was used to identify the mechanism of gentamicin susceptibility. A novel allelic-specific PCR was designed to differentiate gentamicin-sensitive isolates from wild-type B. pseudomallei. A reversion assay was performed to confirm the involvement of this mechanism in gentamicin susceptibility. A substantial proportion (86%) of B. pseudomallei clinical isolates in Sarawak, Malaysian Borneo, were found to be susceptible to the aminoglycoside gentamicin, a rare occurrence in other regions where B. pseudomallei is endemic. Gentamicin sensitivity was restricted to genetically related strains belonging to sequence type 881 or its single-locus variant, sequence type 997. Whole-genome sequencing identified a novel nonsynonymous mutation within amrB, encoding an essential component of the AmrAB-OprA multidrug efflux pump. We confirmed the role of this mutation in conferring aminoglycoside and macrolide sensitivity by reversion of this mutation to the wild-type sequence. Our study demonstrates that alternative B. pseudomallei selective media without gentamicin are needed for accurate melioidosis laboratory diagnosis in Sarawak. This finding may also have implications for environmental sampling of other locations to test for B. pseudomallei endemicity.
Fulltext Global and regional dissemination and evolution of Burkholderia pseudomallei

Chewapreecha C, Holden MT, Vehkala M, Välimäki N, Yang Z, Harris SR, et al.

Nat Microbiol, 2017 Jan 23;2:16263.
PMID: 28112723 DOI: 10.1038/nmicrobiol.2016.263

The environmental bacterium Burkholderia pseudomallei causes an estimated 165,000 cases of human melioidosis per year worldwide and is also classified as a biothreat agent. We used whole genome sequences of 469 B. pseudomallei isolates from 30 countries collected over 79 years to explore its geographic transmission. Our data point to Australia as an early reservoir, with transmission to Southeast Asia followed by onward transmission to South Asia and East Asia. Repeated reintroductions were observed within the Malay Peninsula and between countries bordered by the Mekong River. Our data support an African origin of the Central and South American isolates with introduction of B. pseudomallei into the Americas between 1650 and 1850, providing a temporal link with the slave trade. We also identified geographically distinct genes/variants in Australasian or Southeast Asian isolates alone, with virulence-associated genes being among those over-represented. This provides a potential explanation for clinical manifestations of melioidosis that are geographically restricted.
Fulltext Pediatric melioidosis in Sarawak, Malaysia: Epidemiological, clinical and microbiological characteristics

Mohan A, Podin Y, Tai N, Chieng CH, Rigas V, Machunter B, et al.

PLoS Negl Trop Dis, 2017 Jun;11(6):e0005650.
PMID: 28599008 DOI: 10.1371/journal.pntd.0005650

BACKGROUND: Melioidosis is a serious, and potentially fatal community-acquired infection endemic to northern Australia and Southeast Asia, including Sarawak, Malaysia. The disease, caused by the usually intrinsically aminoglycoside-resistant Burkholderia pseudomallei, most commonly affects adults with predisposing risk factors. There are limited data on pediatric melioidosis in Sarawak.
METHODS: A part prospective, part retrospective study of children aged <15 years with culture-confirmed melioidosis was conducted in the 3 major public hospitals in Central Sarawak between 2009 and 2014. We examined epidemiological, clinical and microbiological characteristics.
FINDINGS: Forty-two patients were recruited during the 6-year study period. The overall annual incidence was estimated to be 4.1 per 100,000 children <15 years, with marked variation between districts. No children had pre-existing medical conditions. Twenty-three (55%) had disseminated disease, 10 (43%) of whom died. The commonest site of infection was the lungs, which occurred in 21 (50%) children. Other important sites of infection included lymph nodes, spleen, joints and lacrimal glands. Seven (17%) children had bacteremia with no overt focus of infection. Delays in diagnosis and in melioidosis-appropriate antibiotic treatment were observed in nearly 90% of children. Of the clinical isolates tested, 35/36 (97%) were susceptible to gentamicin. Of these, all 11 isolates that were genotyped were of a single multi-locus sequence type, ST881, and possessed the putative B. pseudomallei virulence determinants bimABp, fhaB3, and the YLF gene cluster.
CONCLUSIONS: Central Sarawak has a very high incidence of pediatric melioidosis, caused predominantly by gentamicin-susceptible B. pseudomallei strains. Children frequently presented with disseminated disease and had an alarmingly high death rate, despite the absence of any apparent predisposing risk factor.