Scientists find mechanism that leads to drug resistance in bacteria causing melioidosis

gm349 — Mon, 10 Oct 2011 16:46:13 +0000

Researchers have identified a novel mechanism whereby the organism Burkholderia pseudomallei – the cause of melioidosis, a neglected tropical infectious disease – develops resistance to ceftazidime, the standard antibiotic treatment. ̽��ֱ��change also makes the drug-resistant bacterium difficult to detect.

B. pseudomallei is found in water and soil predominately in tropical climates and especially in South East Asia. It can infect both humans and animals and causes melioidosis. ̽��ֱ��disease often occurs in people who have underlying diseases such as type 2 diabetes or renal disease. Symptoms range from relatively mild to severe, and the mortality rate in Asia is as high as four out of ten cases.

Infection is treated using ceftazidime, a third-generation cephalosporin β-lactam antibiotic, which is a derivative of penicillin. This drug is often required for several weeks, during which the bacteria may develop resistance to it. Now, in a paper published in the Proceedings of the National Academies of Science, researchers from the Wellcome Trust-Mahidol ̽��ֱ��-Oxford Tropical Medicine Research Programme in Bangkok, Thailand, and the ̽��ֱ�� of Cambridge, in collaboration with Colorado State ̽��ֱ�� and Genome Institute of Singapore, have identified how the bacteria develop this resistance.

By comparing the genetic make-up of isolates taken from six patients that had become resistant to ceftazidime against their original infecting ceftazidime-susceptible strain, the researchers found a common, large-scale genomic loss involving at least 49 genes that is thought to arise spontaneously as the bacteria replicate and mutate. ̽��ֱ��researchers were able to demonstrate that a specific gene within this region was the cause of the drug resistance. This gene provides the genetic ‘code’ to create a protein that is important to bacterial cell division and that is normally the target for ceftazidime.

̽��ֱ��researchers , who were funded by the Wellcome Trust, also found that these mutated forms of B. pseudomallei would not grow in common laboratory cultures, including bottles that are normally used to culture blood from people with bacterial infections, as well as the routine culture media used in the diagnostic laboratory. This makes the detection of the drug-resistant forms very difficult. Consequently, patients carrying this strain could continue to be treated with drugs that have become ineffective.

Professor Sharon Peacock, the team lead and a professor of clinical microbiology at both Mahidol ̽��ֱ�� and the ̽��ֱ�� of Cambridge, said: “Clinical treatment failure occurs in as many as one in six patients receiving ceftazidime for melioidosis. ̽��ֱ��mechanism described here represents the first explanation for failure of ceftazidime therapy, may be a frequent but undetected event, and provides us with an opportunity to seek ways to increase detection of these variants.”

Commenting on the research, Professor Danny Altmann, Head of Pathogens, Immunology and Population Health at the Wellcome Trust, said: “ ̽��ֱ��development of drug resistance is a major concern for doctors, particularly in low and middle income countries. This study helps us understand how resistance can occur and can hopefully lead to better detection and treatment of drug-resistant forms of melioidosis, a life-threatening tropical disease.”

Researchers have identified a novel mechanism whereby the organism Burkholderia pseudomallei that causes melioidosis, a neglected tropical infectious disease, develops resistance to the standard antibiotic treatment.

Clinical treatment failure occurs in as many as one in six patients receiving ceftazidime for melioidosis. ̽��ֱ��mechanism described here represents the first explanation for failure of ceftazidime therapy, may be a frequent but undetected event, and provides us with an opportunity to seek ways to increase detection of these variants.

Professor Sharon Peacock, the team lead and a professor of clinical microbiology at both Mahidol ̽��ֱ�� and the ̽��ֱ�� of Cambridge

Sharon Peacock

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Diabetes drug improves survival from life-threatening infectious disease

ns480 — Mon, 14 Mar 2011 11:31:13 +0000

Melioidosis, caused by a soil dwelling bacterium (Burkholderia pseudomallei) that is present in certain regions of the world, results in severe infections include bloodstream infections and pneumonia. Death results in up to 40% of affected individuals despite antibiotic treatment. New research by a multinational team from the United Kingdom, Thailand, Singapore and ̽��ֱ��Netherlands, however, has found that people taking the diabetes drug glibenclamide (called glyburide in the US) have half the mortality of other patients with melioidosis.

̽��ֱ��investigators were supported by the Wellcome Trust Thailand/Laos Major Overseas Programme to study 1160 patients with melioidosis in northeast Thailand, and found that death from melioidosis was only 28% in diabetic patients taking glyburide, compared to a mortality rate of nearly one half in other patient groups including those on other diabetes medication and non-diabetics. A study of white blood cells from people taking glibenclamide, performed by collaborators at the Wellcome Trust Sanger Institute, also showed less evidence of activity relating to inflammation.

"Roughly half of all patients with melioidosis have diabetes as a risk factor," says Dr. Gavin Koh, an infectious diseases doctor at the ̽��ֱ�� of Cambridge and first author of the study. "Our Thai collaborators realised several years ago that diabetics are more likely to get melioidosis, but are less likely to die from their infection compared with non-diabetics. Our research shows that this improvement in survival is not an effect of diabetes itself, but of glibenclamide which is often prescribed to control the high blood sugar of diabetes."

Glibenclamide does not appear to have a direct effect on the bacterium, and researchers hypothesise that its benefit comes from modulation of the human immune response to infection. This raises the important possibility that it might have the same benefit in people infected with other pathogens.

"Glibenclamide cannot be given safely to people who present to hospital with severe bacterial infection who are not diabetic," cautions Professor Peacock, Professor of Clinical Microbiology in the Department of Medicine and senior investigator on the study, "but we hope that our findings will result in further research to define the mechanisms by which the drug increases patient survival, and to the development of related drugs that share these mechanisms but that do not lower blood sugar levels and can be given safely to all patients with severe sepsis."

̽��ֱ��study was funded by the Wellcome Trust of Great Britain and was published online by Clinical Infectious Diseases.

Scientists have identified a diabetes drug which halves the mortality rate of a deadly infectious disease found throughout Southeast Asia and Northern Australia.

Roughly half of all patients with melioidosis have diabetes as a risk factor.

Dr. Gavin Koh

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̽��ֱ�� of Cambridge - Melioidosis

Scientists find mechanism that leads to drug resistance in bacteria causing melioidosis

Diabetes drug improves survival from life-threatening infectious disease