If antibiotics don't help…
GM bacteriophages were first used to treat antibiotic-resistant infection
Andrey Ukrainsky, N+1
Scientists have used bacteriophages for the first time to treat mycobacterial infection in humans. An article published in Nature (Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus) states that this is the first case of medical use of genetically modified bacteriophages. In the described clinical case, the condition of a fifteen-year-old patient with cystic fibrosis and chronically infected Mycobacterium abscessus, significantly improved after innovative treatment.
The resistance of pathogens to antimicrobial drugs claims at least 700,000 lives a year, without effective control of this problem by 2050, this figure could grow to one million deaths annually. Mycobacterial infections make a significant contribution to infectious morbidity and mortality: for example, about 230,000 people die from polyresistant tuberculosis per year. Antibiotic-resistant non-tuberculosis mycobacterial diseases are also widespread, in particular, patients with cystic fibrosis often suffer from them. Chronic infections can cause complications and death after lung transplantation, which is often required by such patients.
Bacteriophages (viruses that infect bacteria) can become an alternative to antibiotics, but they have not previously been used to treat mycobacterial infections in humans. At the same time, personalized intravenous phage therapy for other infections has already been described (1, 2).
Rebekah M. Dedrick and Carlos A. Guerrero-Bustamante from the University of Pittsburgh together with colleagues described a clinical case of a fifteen-year-old girl with cystic fibrosis and chronically infected with an antibiotic-resistant strain Mycobacterium abscessus of the subspecies massiliense. The disease was accompanied by several concomitant pathologies, including pancreatic insufficiency, insulin-dependent diabetes mellitus and liver damage associated with the underlying disease.
The patient underwent successful bilateral lung transplantation. For eight years prior to this operation, she received specific therapy against a non-tuberculosis mycobacterial infection. The transplantation went without complications, after which the girl received immunosuppressive therapy and antibiotics. After transplantation, M.abscessus was found in the sputum, the liver was enlarged, functional liver tests were pathological. A week after completing the course of intravenous antibiotics, the postoperative wound was inflamed, skin lesions appeared on the forearm.
The patient was discharged from the hospital after seven months with a diagnosis of disseminated mycobacterial infection. Despite the continuation of the antimicrobial treatment, skin lesions in the form of nodules continued to appear on different parts of the body, the condition of the surgical wound worsened.
Since antibiotic treatment had no effect, the scientists decided to carry out treatment with bacteriophages. To select potentially suitable phages, they used a culture of the GD01 strain of M.abscessus isolated from a patient a month after surgery. They turned to a collection that included more than 10,000 phages, the genome of 1800 of which was known. Only one bacteriophage, Muddy, was found that could effectively kill mycobacteria of the GD01 strain. The effectiveness of the second selected bacteriophage, ZoeJ, was low, so scientists used the method of genetic engineering Bacteriophage Recombineeringof Electroporated DNA (BRED) to increase its therapeutic power. For the third selected phage, BPs, which initially weakly infected M.abscessus, the authors isolated mutants with an altered spectrum of lytic action (HRM1 and HRM10).
All three phages belong to siphoviruses (Siphoviridae). In laboratory experiments, ZoeJ and BPs were less effective than Muddy, but a mixture of three bacteriophages in vitro did not leave any M.abscessus alive even at its high concentrations.
Scientists injected the patient with a prepared mixture of three phages (109 plaque-forming units of each phage) intravenously every 12 hours, treatment was scheduled for approximately 32 weeks. The patient was discharged from the hospital after nine days, treatment continued at home. During the first two hours of treatment, the patient had sweating, she experienced hot flashes, but otherwise the treatment was well tolerated: no other side effects were recorded. After a month of therapy, local treatment with bacteriophages was added in places of skin lesions.
Within six months (by the time of writing the article), the patient's condition gradually improved: the postoperative wound healed, lung and liver functions improved, she began to gain weight, although the wound on the sternum was not completely healed. Positron emission tomography showed improvements in internal organs and skin nodules. M.abscessus was not detected in sputum and blood from the first day of treatment, but was still isolated from skin nodules.
Images obtained using positron emission tomography 12 weeks before treatment and six weeks after it. 1) the sternum area and surrounding soft tissues, 2) abdominal lymph nodes and liver gates, 3) skin nodules. A drawing from an article in Nature.
Scientists note that the phages discovered and modified by them are not a universal means of therapy against M.abscessus. So, they were not effective for the GD02 strain, which was isolated from another patient.
The authors write that, according to their information, this was the first case of the therapeutic use of bacteriophages in mycobacterial infection in humans, as well as the first case of the use of genetically engineered phages. Although phage treatment was associated with an improvement in the patient's condition, scientists do not exclude the possibility that similar effects could have occurred without it: one clinical case does not allow conclusions to be drawn. But they point out that there is usually a high morbidity and mortality among patients with similar conditions. In addition, the improvement of their patient's condition was not associated with the beginning or completion of other types of therapy.
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