Multidrug Resistant Bacteria’s Latest Mechanism To Block Colistin Revealed

Highlights:

Investigators discover the mechanism by which Acinetobacter baumannii resists colistin, the antibiotic that is usually used as a last resort in hospital-acquired infections.
A.baumannii strains are already resistant to most known antibiotics.
Understanding why and how the bacteria resists colistin in clinical settings can help in identifying treatments to circumvent or minimize the resistance.

Australian and Portuguese investigators have discovered another resistance mechanism in Acinetobacter baumannii, an opportunistic bacterial pathogen by which it blocks colistin, an antibiotic-of-last resort.

The study is published in Antimicrobial Agents and Chemotherapy, a journal of the American Society for Microbiology.

Portuguese clinicians discovered that A. Baumannii from a bloodstream infection remained in an elderly patient even after treatment. Due to the multidrug-resistant nature of the strain, the patient was being treated with colistin as a last-resort.

"The infection could not be cleared as the strain developed high-level colistin resistance during treatment," said Dr. Boyce, who is Associate Professor, Infection and Immunity Program, Monash Biomedicine Discovery Institute, and Department of Microbiology, Monash University, Melbourne, Australia.

Hospital Acquired Infections | Nosocomial Infections - Types, Causes, Symptoms, Risk Factors, Diagnosis, Treatment and Prevention
Hospital acquired infections (HAI) are acquired by patients and health personnel alike in a hospital setting. HAI can be life-threatening and need to be promptly diagnosed and treated. Major causes are bacteria, with fungi and viruses playing a lesser role.

‘Researchers have found yet another mechanism by which the already highly multidrug-resistant bacteria, Acinetobacter baumanni resists the antibiotic colistin used primarily in hospital settings.’

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Acinetobacter baumannii

Acinetobacter baumannii is a gram-negative bacillus that is primarily associated with hospital-acquired infections. It is widespread and primarily infects patients in intensive care units with ventilator-associated pneumonia, bloodstream infections, and urinary tract infections.

A.baumannii infections were earlier thought to be acquired at the site of injury, but the bacteria has a remarkable ability to survive on exterior surfaces for extended periods. It spreads through direct contact with surfaces, objects, and the skin of contaminated persons. In war zones of Iraq and Afghanistan, the bacteria spread quickly since the soldiers got transported across different medical facilities in the combat zones.

It is also known as ‘Iraqibacter’ since its recent increase in incidence occurred largely due to the infected combat troops returning from conflict zones.

Currently, there are A. Baumanii strains that are resistant to most known antibiotics. Its emerging resistance profile and ability to survive for long periods throughout a hospital environment has boosted its capacity for a nosocomial spread.

The Centres for Disease Control and Prevention (CDC) defines a nosocomial infection as one that has been acquired 48 hours after admission into a hospital setting.

The organism poses little risk to healthy individuals but targets the most vulnerable hospitalized patients; this usually refers to individuals with a weakened immune system, chronic lung disease, diabetes and those staying at hospitals for a lengthened period, and patients using a hospital ventilator or invasive devices like urinary catheters.

Bacteremia - Causes, Symptoms, Diagnosis, Treatment, Prevention
Bacteremia is the presence of viable bacteria in the bloodstream. Blood cultures are used in diagnosis and antibiotics are used to treat bacteremia.

Study – The reason why A.baumannii is highly colistin resistant

To understand this, the investigators determined whole genome sequences of the microorganism isolates before and after treatment with colistin.

The sequences were compared to find out what genetic changes are caused in the organism if it acquires a high level of colistin resistance.

Quiz on Urinary Tract Infections (UTIs)
A urinary tract infection is infection of the kidneys, ureters, bladder, and urethra. Take the following quiz to test your knowledge about this commonly occurring infection.

Results of the study

The histone-like nucleoid-structuring or the hns gene encodes a protein (H-NS) that regulates gene transcription. The investigators found that the gene’s normal expression had been disrupted by an insertion sequence element (DNA sequence that can insert itself into a chromosome). The disruption of a transcription regulator would, in turn, change the expression of many other genes in the bacteria.

To find why the disruption of the hns gene affected colistin resistance, the investigators compared the transcription products of genes from pre- and post-treatment isolates and discovered that after treatment the organisms had more expression of a gene that could boost colistin resistance.

To confirm that it was indeed the disruption of hns that was responsible for the resistance the hns gene was inactivated in the non-resistant strain; this caused that strain to become "highly colistin resistant”.

"Colistin is a 'last resort' antibiotic that is generally used to treat infections caused by bacteria that are resistant to all other antibiotics," said Dr. Boyce. "Development of colistin resistance in strains that are already multidrug-resistant is incredibly alarming; the threat of pan-resistant infections is very real... development of high-level colistin resistance in this instance played a major role in treatment failure and led to an infection that could not be resolved (although the patient had other comorbidities)."

Dr. Boyce also said that researchers have to understand the mechanisms behind the development of colistin resistance in clinical settings. This can help in identifying treatments that minimize or circumvent resistance development and help in developing drugs that target the regulatory systems that control resistance in the future.

Colistin

Colistin or polymyxin E is an old antibiotic that belongs to a group of cationic polypeptide antibiotics known as polymyxins. Colistin was introduced more than 50 years ago and used for the treatment of infections caused by Gram-negative bacilli. Its use was stopped due to its side effects of nephrotoxicity and neurotoxicity, and it was then replaced with safer antibiotics.

Now due to the rise of nosocomial infections caused by gram-negative and multidrug-resistant (MDR) bacteria, colistin has re-emerged as an alternative treatment against gram-negative MDR organisms. Colistin is now an antibiotic-of-last-resort used in hospital-acquired infections against MDR gram-negative organisms, mostly P. Aeruginosa and A. Baumannii responsible for pneumonia, bacteremia, and urinary tract infections.

Recently, colistin is used in combination with other antibiotics for increased antibacterial efficacy. It is probable that colistin will be the future therapeutic drug against multidrug-resistant gram-negative infections and as an alternative to antibiotics that have been available so far.

References:

Kouchak F, Askarian M. “Nosocomial Infections: The Definition Criteria”. Iranian Journal ofMedical Sciences. (2012); 37(2):72-73.
Howard A, O’Donoghue M, Feeney A, Sleator RD. “Acinetobacter baumannii: Anemerging opportunistic pathogen”. Virulence. (2012);3(3):243-250. doi:10.4161/viru.19700.
Gupta S, Govil D, Kakar PN, et al. “Colistin and polymyxin B: A re-emergence”. Indian Journal of Critical Care Medicine: Peer-reviewed, Official Publication of Indian Society of Critical CareMedicine. (2009);13(2):49-53. doi:10.4103/0972-5229.56048.
Peleg AY, Seifert H, Paterson DL.“Acinetobacter baumannii: Emergence of a Successful Pathogen”. Clinical Microbiology Reviews. (2008);21(3):538-582.doi:10.1128/CMR.00058-07.
Acinetobacter baumannii - (https://en.wikipedia.org/wiki/Acinetobacter_baumannii)

Source-Medindia