Please use this identifier to cite or link to this item: http://docs.prosentient.com.au/prosentientjspui/handle/1/10597
Title: Raising the stakes: Loss of efflux-pump regulation decreases meropenem susceptibility in Burkholderia pseudomallei.
Authors: Sarovich, Derek S
Webb, Jessica R
Pitman, Matthew C
Viberg, Linda T
Mayo, Mark
Baird, Robert W
Robson, Jennifer M
Currie, Bart J
Price, Erin P
Affiliation: Global and Tropical Health Division, Menzies School of Health Research, Tiwi, Northern Territory, Australia.. Faculty of Science, Health, Education and Engineering, University of the Sunshine Coast, Sippy Downs, Queensland, Australia..
Global and Tropical Health Division, Menzies School of Health Research, Tiwi, Northern Territory, Australia..
Department of Pathology, Royal Darwin Hospital, Tiwi, Northern Territory, Australia.. Department of Infectious Diseases, Royal Darwin Hospital, Tiwi, Northern Territory, Australia..
Global and Tropical Health Division, Menzies School of Health Research, Tiwi, Northern Territory, Australia..
Global and Tropical Health Division, Menzies School of Health Research, Tiwi, Northern Territory, Australia..
Department of Pathology, Royal Darwin Hospital, Tiwi, Northern Territory, Australia.. Department of Infectious Diseases, Royal Darwin Hospital, Tiwi, Northern Territory, Australia..
Sullivan Nicolaides Pathology, Bowen Hills, Queensland, Australia..
Global and Tropical Health Division, Menzies School of Health Research, Tiwi, Northern Territory, Australia.. Department of Infectious Diseases, Royal Darwin Hospital, Tiwi, Northern Territory, Australia.. Northern Territory Medical Program, Royal Darwin Hospital, Tiwi, Northern Territory, Australia..
Global and Tropical Health Division, Menzies School of Health Research, Tiwi, Northern Territory, Australia.. Faculty of Science, Health, Education and Engineering, University of the Sunshine Coast, Sippy Downs, Queensland, Australia..
Issue Date: 31-Jan-2018
Citation: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2018-01-31
Abstract: Burkholderia pseudomallei, the causative agent of the high-mortality disease melioidosis, is a Gram-negative bacterium that is naturally resistant to many antibiotics. There is no vaccine for melioidosis, and effective eradication is reliant on biphasic and prolonged antibiotic administration. The carbapenem drug, meropenem, is the current gold-standard option for treating severe melioidosis. Intrinsic B. pseudomallei resistance towards meropenem has not yet been documented; however, resistance could conceivably develop over the course of infection, leading to prolonged sepsis and treatment failure. We examined our 30-year clinical collection of melioidosis cases to identify B. pseudomallei isolates with reduced meropenem susceptibility. Isolates were subjected to minimum inhibitory concentration (MIC) testing towards meropenem. Paired isolates from patients that had evolved decreased susceptibility were subjected to whole-genome sequencing. Select Agent-compliant genetic manipulation was carried out to confirm the molecular mechanisms conferring resistance. We identified 11 melioidosis cases where B. pseudomallei isolates developed decreased susceptibility towards meropenem during treatment, including two cases not treated with this antibiotic. Meropenem MICs increased from 0.5-0.75 to 3-8 µg/mL. Comparative genomics identified multiple mutations affecting multidrug resistance-nodulation-division (RND) efflux pump regulators, with concomitant over-expression of their corresponding pumps. All cases were refractory to treatment despite aggressive, targeted therapy, and two were associated with a fatal outcome. This study confirms the role of RND efflux pumps in decreased meropenem susceptibility in B. pseudomallei. These findings have important ramifications for the diagnosis, treatment and management of life-threatening melioidosis cases.
URI: http://docs.prosentient.com.au/prosentientjspui/handle/1/10597
DOI: 10.1093/cid/ciy069
Type: Journal Article
Subjects: AmrR
Burkholderia pseudomallei
RND efflux pump
antibiotic resistance
carbapenem
comparative genomics
decreased susceptibility
meropenem
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