Two on one
Bacteriophage and antibiotic saved the patient from drug-resistant infection
Ekaterina Rusakova, N+1
The bacteriophage OMKO1 with the antibiotic ceftazidime was able to rid the patient of an infection that had been unsuccessfully treated with traditional antibiotics for several years, according to the journal Evolution, Medicine and Public Health (Chan et al., Phage treatment of an aortic graft infected with Pseudomonas aeruginosa). A patient with an aortic aneurysm had an implant installed, but after surgery he developed an infection caused by Pseudomonas aeruginosa.
Pseudomonas aeruginosa (Pseudomonas aeruginosa) has increased resistance to most antibiotics and belongs to the so-called ESKAPE pathogens – bacteria that cause hospital infections around the world. In particular, it is found in abscesses and purulent wounds. Treatment of infections caused by P.aeruginosa is complicated by the fact that bacteria form biofilms on the surface of the affected organ. Antibiotics do not act on this bacterial community, but destroy only individual (planktonic) bacteria that the biofilm emits.
To destroy ESKAPE pathogens, researchers are trying alternative options, including treatment with bacteriophages. Bacterial viruses can penetrate the biofilm and destroy the bacteria that it consists of. The method of treatment with bacteriophages began to be developed almost 100 years ago, shortly after the discovery of these microorganisms. However, this method has disadvantages: the procedure for selecting the right phages acting on a particular type of bacteria takes at least a few days, they can only be treated on the outer surfaces of the body or intestines, besides phages begin to multiply at a high concentration of bacteria, the destruction of which can cause a toxic shock in the patient. In addition, bacteria develop resistance to bacteriophages, as well as to antibiotics, so currently bacteriophages are rarely used.
Scientists from Yale University, led by surgeon Deepak Narayan and evolutionary biologist Paul Turner, decided to use the bacteriophage OMKO1 to treat a patient with a severe hospital infection. In 2012, a 76-year-old patient underwent surgery for an aortic arch aneurysm and a dacron implant was installed. Shortly after the operation, the patient developed an infection caused by Pseudomonas aeruginosa. To combat it, the man repeatedly underwent surgical cleaning of the chest (made a drainage hole through which the pus came out) and prescribed multiple long courses of antibiotics. But the treatment did not help, the patient's condition worsened. Doctors believed that it was too risky to perform a repeat operation, and decided to conduct experimental treatment with bacteriophage and the antibiotic ceftazidime, which is used to treat Pseudomonas aeruginosa.
As a candidate, they chose the OMKO1 phage, which was obtained from pond water samples. The researchers took them to Dodge Pond 65 kilometers from Yale University. As the authors of the study found out in their previous work, OMKO1 attaches to the membrane of Pseudomonas aeruginosa, more precisely, to a pump protein that "pumps" the antibiotic out of the cell before it has time to act. The researchers suggested that P.aegidipos had developed resistance to phage by mutations in the membrane pump that prevented OMKO1 binding. But these same mutations reduce the efficiency of the "pump" and make the bacterium vulnerable to the antibiotic. Therefore, according to scientists from Yale, combination therapy should have helped the patient.
The scheme of action of the drug proposed by scientists. The antibiotic in therapeutic concentrations cannot penetrate biofilms due to its poor permeability and the inhibited metabolism of its components. But the OMKO1 phage is able to multiply in the bacteria forming the film. As a result, the stability of the bacterial film is disrupted, and then it begins to collapse. And then even therapeutic amounts of the antibiotic act on pathogens. And bacteria resistant to phage become more sensitive to the antibiotic. A drawing from an article in Evolution, Medicine and Public Health.
Before conducting treatment, the authors of the work conducted laboratory experiments and were convinced of the effectiveness of the action of ceftazidime and phage on biofilms of Pseudomonas aeruginosa, which was obtained from the patient's secretions. The researchers suggested that OMKO1 destroys individual bacteria by destabilizing the bacterial film. After that, the antibiotic gets access to individual bacteria resistant to the phage and destroys them.
In 2016, after the success of laboratory experiments, and obtaining permission for surgery from the FDA and the university administration, doctors injected a suspension of OMKO1 phage and ceftazidime into the patient's chest. After the procedure, he was prescribed a short course of ceftazidime. As a result, there were no relapses of infection in the man for 18 months (before the article was submitted to the press).
Recently, Singapore researchers synthesized a polymer that effectively destroys ESKAPE pathogens, including Pseudomonas aeruginosa. Unlike antibiotics, the new substance is low-toxic and does not cause resistance in bacteria.
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