Bacteriophage therapy is an alternative therapy that has long been successfully used to treat Staphylococcal infections, in some parts of the world, including Georgia, and is drawing new interest worldwide in this era of antibiotic resistance (6). Bacteriophages are bacterial viruses that are highly specific for their host. The phage injects its DNA into the bacterial cell and takes over the host to produce phage progeny, soon lysing the cell to release phage which will go on to further infect new bacterial hosts. Phage therapy has been used been successfully used as antibacterial treatment in the former Soviet Union, France, and the USA, particularly in the pre-antibiotic era. Their use in humans is not considered to be experimental because of their extensive history of use there. Phage therapy is now drawing new interest worldwide in this era of antibiotic resistance (7). However, despite its rich history and long record of apparent safety, double blind controlled trials are only now beginning to be carried out to prove its efficacy up to modern standards for the treatment of various diseases. Compassionate use case studies are still an important source of information about its potential. The Eliava Phage Therapy Center was established 7 years ago by the Eliava Foundation, a non-profit organization made up of Eliava scientists and the Eliava Institute, to facilitate more direct focus on the use of phage, documentation of the consequences, and access to phage therapy for people coming from other countries and often continuing treatment once they return home.

On examination, physical delays were noted: height 150 cm, weight—40 kg (both falling below the fifth percentile), while intellectual development was observed to be normal. His hair was lusterless, sparse, beaded, and easily broken, 4–5 cm in length, with sparse eyebrows and eye lashes. Skin changes noted were typical for NS: cracked, dry, skin, and the entire body covered with a serpiginous yellowish thick film, which was more prominent on the face and knees. The tightness of the skin restricted mobility of the knees and arms, preventing complete extension. Hyperkeratization was observed on both the palms and soles of the feet. He also had severe pruritus.

The complete blood count was normal, but ESR was slightly increased. Biochemical markers were normal. Bacteriological analysis of swabs taken from affected areas on the skin showed strong growth of S. aureus. This bacterial infection had been present for the last 4 years and was the main complication of the disease. The treatment of this infection was hindered due to antibiotic resistance of the strain and the patient’s individual allergies to multiple antibiotics. These were the main motivating factors for the patient’s family to seek alternative treatment and to approach our clinic in regards to phage therapy. We chose two Staphylococcus-targeting phage preparations, based on phage sensitivity testing—Staphylococcus bacteriophage, containing fully sequenced Sb1 phage (8), and Pyobacteriophage targeting Staphylococcus spp., Streptococcus spp., E. coli, Pseudomonas aeruginosa, and Proteus spp., both to be used per os and externally.

Due to the patients’ allergic predisposition, phage was first only applied in a 1 cm² area and was observed for 2 h. No adverse reactions were seen, and daily procedures were then carried out. First, the patient’s limbs were wrapped with sterile gauze (Figure 1) and liquid Pyobacteriophage was sprayed on with a sterile syringe to soak the gauze. After 20 min, the gauze was removed and a thin layer of Staphylococcus bacteriophage cream was applied. This cream was specially prepared in the Eliava Authorized Compounding Pharmacy using a hypoallergenic cream base, which the patient provided as previous use of this cream alone had not given him an allergic reaction. The cream was allowed to adsorb. The patient bathed with his regular hygenic regime each morning before the next treatment. Oral treatments with two phage preparations—Pyobacteriophage 10 ml once daily and Staphylococcus bacteriophage 10 ml once daily—were also taken after first neutralizing the stomach acid with 100 ml of “Borjomi” alkaline mineral water.

The initial phage treatment was carried out for 20 days, after which the patient took a 2-week pause and continued treatment for another 20 days. Repeat bacteriological testing performed after 3 months, identified S. aureus and Streptococcus, which was sensitive to “Fersis” (which targets Staphylococcus spp. and Streptococcus spp.) bacteriophage (Table 2). During the second 3 month period, the patient took phage for 2 week periods, with 2-week breaks in between treatment courses.

Baseline scores for NASA were determined initially and compared with values obtained during treatment. Peak reductions from NASA baselines ranged from 18.4 to 11.2 after 3 months and 7.8 after 6 months of phage therapy. During the 6-month observation period, no eosinophilia was noted at baseline. No clinically significant abnormalities were observed in complete blood cell counts, hepatic function testing, electrolytes, or glucose monitoring.

Microbiological testing was done before intervention; qualitative bacterial cultures and culture sensitivities of the eyes, nostrils, and the worst, overtly infected lesions on the skin were obtained. At 3 and 6 months after the initiation of phage therapy, repeat swabs were obtained. The results showed a significant decrease in S. aureus in the eye and nostrils, while strong growth from the skin swab remained, indicating the need for prolonged treatment with periodic microbiological testing. Phage sensitivity profiles showed resistance to Pyobacteriophage after 3 months of treatment, after which an alternate phage cocktail was substituted to the treatment scheme.

Similar improvements were seen using the IGED, which was graded on a 5-point, 0–4 scale. A peak reduction of IGED scores of 55% was evident after 3 months treatment to 75% after 6 months treatment with phage.

On a follow-up visit 3 months later, regeneration of the skin had continued and the symptoms have not returned. Significant improvement was seen on the legs, especially around the knee joints, which were extremely tight and immobile, as well as the arms and face.

At a 6-month follow-up, the patients’ condition was stable. His skin continued to improve visually and he had not required hospitalization for generalized infection since starting phage therapy (See Figures S1 and S2 in Supplementary Material).

A total of 100 years after the discovery of bacteriophage, their role in medicine is of recurrent interest but still not secure. Viruses that attack bacteria were first observed by Twort and d’Herelle in 1915 and 1917. During the 1920s and 1930s the young Georgian microbiologist, G. Eliava, headed the Institute of Microbiology in Tbilisi. Eventually founding an institute in Tbilisi which continued on to be the largest producer of bacteriophage preparations in the former Soviet Union preparing bacteriophages to treat a wide range of topical, internal, and respiratory bacterial pathogens. After the fall of the Soviet Union, the institute met a lot of challenges. After years of work and international collaboration, the institute has re-established itself as a leader in bacteriophage research and its various applications in human, as well as in animal, plant, and environment (10). The use and study of phage therapy continues in the Georgia, Russia, and Poland and is increasingly being explored in the Western world as one potential weapon against the devastating rise of antibiotic resistant bacteria (11, 12).

The pharmacokinetics and pharmacodynamics of bacteriophage are complex and still being explored. Animal experiments in the early 1940s showed that phage are widely distributed throughout the body and easily cross the blood brain barrier (13). A more recent study in a pediatric population showed that orally administered phage is excreted into urine, stool, and CSF during administration and is quickly eliminated from the body, undetectable 3–5 days after cessation of treatment (14). There is much evidence that phages are safe for use (7, 10–12). There is no recorded anaphylactic reaction to phage in the literature. They are self-replicating and self-limited. The specificity of each for a very narrow group of targeted bacteria reduces side effects compared to other antimicrobials, which negatively affect the microbiome.

Despite the long history of successful use, phage therapy has not yet managed to re-enter Western medicine as a viable available treatment option due to a lack of randomized controlled trials, quintessential in the age of evidence based medicine. Many authors note the importance of fast tracking phage therapy, even if only for compassionate use in this era of antibiotic resistance, while definitive randomized controlled trials of various applications are being developed, funded, and carried out (7, 15–18).

The advantages of phage therapy are clear: the ability to easily treat many antibiotic-resistant microbes, antibacterial treatment in cases of drug allergy, and high tolerability with little or no side effects. This case represents the effective use of phage therapy for the treatment of infectious complications of a rare genetic disease, which had extremely limited treatment options. For this French patient, phage therapy represents an essential alternative to control frequent infections and reduce the severity of NS, thus significantly improving his quality of life.