Multidrug Resistant E. Coli Succumbs to a Superteam of Antibiotics

Multidrug Resistant E. Coli Succumbs to a Superteam of Antibiotics

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Highlights:
  • Pathogenic strains of E. coli bacterium are capable of causing serious diseases.
  • E. coli belongs to Carbapenem-resistant Enterobacteriaceae that only respond to last resort antibiotics.
  • A superteam of antibiotics has been found to synergistically suppress E. coli.
Researchers at the University at Buffalo have put together a team of three antibiotics that, together, are capable of wiping out the deadly bacterium, E.coli. This research was recently published in mBio, a journal for the American Society of Microbiology.
Multidrug Resistant E. Coli Succumbs to a Superteam of Antibiotics

This groundbreaking study has been completed at a crucial moment when researchers were just starting to feel that the golden age of antibiotics may be coming to a close.

Escherichia coli or E. coli

Antibiotics are given either to treat bacterial infections or to prevent them. Antibiotic resistance occurs when bacteria undergo changes so that drugs, and other agents used against them become ineffective. The bacteria, thus become antibiotic-resistant and survive and continue to proliferate, further harming the individual.

Escherichia coli or E. coli is a rod-shaped, gram-negative bacterium belonging to the genus Escherichia. Most of the strains of E. coli are harmless and thrive in the lower intestine or gut of humans and other warm-blooded organisms. They live in a symbiotic relationship with pathogenic or harmful bacteria preventing their colonization. Some virulent strains of E. coli living inside and outside the gut can cause gastroenteritis, urinary tract infections, neonatal meningitis, wound infections, pneumonia and Crohn's disease.

E. coli belongs to a family of microorganisms called Enterobacteriaceae that can cause infections in both healthcare and community settings. Enterobacteriaceae that are resistant to a group of antibiotics called Carbapenems are called Carbapenem-resistant Enterobacteriaceae or CRE. As such, Carbapenems are reserved to treat serious infections and sometimes used as a last resort for certain infections that do not respond to any other antibiotics. The germs causing these infections are difficult to treat because they produce an enzyme called carbapenemase that disables the drug molecule, thus rendering high levels of resistance. CRE are considered an emerging threat to global public health.

(After the emergence of resistance to third-generation cephalosporins by extended-spectrum β-lactamases (ESBLs) has led to an increased use of carbapenem compounds)

New Delhi metallo-β-lactamase (NDM) and mobilized colistin resistance (mcr-1)

Among the newly emerged and most widespread carbapenemases, is a kind called New Delhi metallo-β-lactamase (NDM-first described in 2008), whose latest new variant NDM-5 was identified in a multidrug-resistant E.coli. It represents the latest threat to public health. NDM is an enzyme that makes bacteria resistant to a broad range of beta-lactam antibiotics which include the antibiotics of the carbapenem family. The gene for NDM-1 encodes beta-lactamase enzymes called carbapenemases. Bacteria that produce carbapenemases are often referred to as "superbugs" because of the incurable nature of the infections they cause. Usually these bacteria only respond to Polymyxins and Tigecycline.

Another gene called the "mobilized colistin resistance" (mcr-1) gene confers plasmid-mediated resistance to Colistin which is a Polymyxin and considered to be one of a number of last-resort antibiotics for treating infections. The gene was first discovered in E. coli from a pig in China in 2011.

Both NDM and MCR-1 have been detected in a few bacteria and very recently two E.coli clones that coproduce NDM-5 and MCR-1 genes have been detected in a single fowl in China, making them resistant to even last-resort antibiotics.

This raised the question whether there will ever be an effective means of treatment for the so-called "superbugs".

Trio of Aztreonam, Amikacin and Polymyxin B

Finally, a novel combination of three antibiotics, Aztreonam, Amikacin and Polymyxin B was able to kill E. coli carrying mcr-1 and ndm-5 genes within 24 hours and prevent them from growing back. Prior traditional combinations of these antibiotics had failed to kill the E. coli and resulted in rapid resistance.

"The threat of gram-negative bacteria, including E. coli carrying mcr-1, is worrisome," says Zackery Bulman, PharmD, first author on the study, a graduate and former postdoctoral fellow at the UB School of Pharmacy and Pharmaceutical Sciences who is now an assistant professor at the University of Illinois at Chicago College of Pharmacy. "We believe that the appearance of mcr-1 and ndm-5 in patients may be a harbinger for what is to come. The golden era of antibiotics isn't over yet, but we wanted to help clinicians prepare therapeutically for the occurrence of these strains."

The mcr-1 and ndm-5 strains pose an imminent threat as they possess a high-degree of resistance as well as rapid transmission in a community setting according to Brian Tsuji, PharmD, principal investigator and associate professor in the School of Pharmacy and Pharmaceutical Sciences, necessitating the urgency to think beyond traditional antibiotic combinations.

This happens to be the first study to come up with treatment measures against superbugs that possess mcr-1 and ndm-5, thereby enabling clinicians to be prepared when they face these pathogens again.

Although reported cases of E. coli carrying the mcr-1 gene are few in the U.S. compared to other countries, one cannot undermine the bacteria's resistance to the currently available antibiotics that makes the worldwide medical community vulnerable to a massive outbreak of infections.

How the new combination of antibiotics was discovered
With an increasing number of antibiotic-resistant bacteria, the medical community had resorted to a class of antibiotics called Polymyxins. These are nonetheless effective, but employed as a last resort because of the damage they can cause to the kidneys. Various antibiotic combinations and dosing strategies of Polymyxins are being tried in order to avoid prescribing high dosages of the drugs.

Dozens of combinations of around 15 or more antibiotics were paired with Polymyxin B and studies were conducted to narrow down on two effective treatments.

Results of the study were -
  • Out of all combinations, when Polymyxin B was paired with either Aztreonam or Amikacin, bacterial counts remained undetectable after 24 hours.
  • However, this lasted only up until 96 hours after which the E. coli was able to grow back to the levels present initially.
  • Moreover, the combination of Polymyxin B and Amikacin caused a regrowth of a subpopulation of Amikacin-resistant strains after 10 days.
  • The combination of Polymyxin B and Aztreonam pushed the E. coli into a state that was persistent but nonreplicating.
  • Finally, it was discovered that only the triple combination was effective in eliminating the E. coli strain and preventing its regrowth.
"We knew that Polymyxins alone couldn't work. Only the three drugs combined were able to work synergistically to suppress and kill the bacteria," says Bulman. "We overcame the bacteria by pushing it as far as possible with an agent that it was resistant to while simultaneously administering two other antibiotics."

Let's hope that this finding provides a possible treatment method against mcr-1 and ndm-5 strains.

Reference:
  1. Zackery P. Bulman, Liang Chen, Thomas J. Walsh, Michael J. Satlin, Yuli Qian, Jürgen B. Bulitta, Charles A. Peloquin, Patricia N. Holden, Roger L. Nation, Jian Li, Barry N. Kreiswirth, Brian T. Tsuji. Polymyxin Combinations Combat Escherichia coli Harboring mcr-1 and bla NDM-5 Preparation for a Postantibiotic Era. mBio,(2017); 8 (4): e00540-17 DOI: 10.1128/mBio.00540-17
  2. Yang R-S, Feng Y, Lv X-Y, Duan J-H, Chen J, Fang L-X, Xia J, Liao X-P, Sun J, Liu Y-H. 2016. Emergence of NDM-5- and MCR-1-producing Escherichia coli clones ST648 and ST156 from a single Muscovy duck (Cairina moschata). Antimicrob Agents Chemother 60:6899-6902. doi:10.1128/AAC.01365-16.
  3. Escherichia coli - (https:en.wikipedia.org/wiki/Escherichia_coli)
  4. Carbapenem-resistant Enterobacteriaceae (CRE) Infection: Patient FAQs - (https:www.cdc.gov/hai/organisms/cre/cre-patientfaq.html)
  5. New Delhi metallo-beta-lactamase 1 - (https:en.wikipedia.org/wiki/New_Delhi_metallo-beta-lactamase_1)
  6. MCR-1 - (https:en.wikipedia.org/wiki/MCR-1)

Source: Medindia

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