Staphylococcus aureus is a gram-positive bacterium that is part of the normal skin microbiome of humans and animals. It is characterized by biofilm formation, high resistance to the environment and rapid gene transfer by plasmids. Due to these factors, S. aureus readily acquires antibiotic resistance and becomes one of the most common causative agents of hospital-acquired infections. Therefore, the World Health Organization has included it in the ESKAPE group, which includes the most dangerous pathogens against which there is the greatest urgency to find new treatments [2]. Biofilms often grow in chronic wounds, on the surface of implants, endoprostheses and invasive medical devices [4].

S. aureus causes a wide range of infections – from numerous skin infections, wound infections, pneumonia to sepsis. It is the causative agent of up to 80% of all nosocomial infections detected [2]. The most problematic are cutaneous infections caused by methicillin-resistant golden staphylococcus aureus, which are by far the most common and new treatment options are therefore the most desirable. In addition to hospital-acquired infections, it also causes community-acquired infections, which mainly affect young and healthy individuals [7].

Phage therapy is emerging as one of the options to effectively combat resistant strains. Phages can multiply at the site of infection without burdening the patient’s organism and its microflora. In addition, it appears that the side effects commonly associated with antibiotic treatment do not occur. Unlike antibiotics, phages can destroy bacterial biofilms because they can penetrate the mass of the biofilm that surrounds and protects them [4]. Numerous studies from all over the world – especially from the United States, China, Poland and other countries – have described that phage therapy for methicillin-resistant golden staphylococcus aureus (MRSA) appears to be a potential option to deal with resistant infections.

The 16-year-old boy, who suffered from severe skin infections, a large number of drug allergies and numerous hereditary diseases, was treated with a phage cocktail that was administered in the form of a cream and solution to the affected areas. After 7 days there was a significant improvement in health status, and after 6 months there was a significant improvement in the patient’s quality of life [1].

After administration of AB-SA01 phage cocktail in diabetic mice with chronic wounds that were infected with MRSA, most of the mice showed complete wound healing. In all mice, the treatment outcome was then better than that of vancomycin treatment both in terms of wound size and the bacterial load detected. No side effects were observed in mice treated with the phage cocktail [3]. There are several similar studies publishing the results of experimental phage therapy in mice [17, 18]. A similar study investigated phage therapy of ulcers infected with S. aureus, P. aeruginosa and A. baumanii in mice and diabetic pigs. Phage therapy significantly reduced bacterial colony counts and improved ulcer healing in infections caused by S. aureus and P aeruginosa. However, treatment did not produce similarly successful results for A. baumanii. Mice also responded better to treatment than pigs [20].

Another study tested the efficacy of a phage cocktail on non-healing wounds in 20 selected patients between 16-20 years of age who were colonized with strains of S. aureus, E. Coli and P. aeruginosa. In total, the wound was treated with the phage cocktail 3 to 5 times. After this application, the size of the wounds was significantly reduced and there was no sign of infection on the wound surface after microbiological examination. In 7 patients, the wound completely healed after 3 weeks [6].

A similar study tested phage therapy for chronic wounds and skin ulcers in 48 patients of whom twenty-one were healthy and 27 had diabetes. Those affected were infected with several species of bacteria simultaneously, including S. aureus. Thirty-nine patients made a complete recovery. The success rate was 90.5% in non-diabetics and 74.1% in diabetics. The tibial ulcers decreased significantly after treatment. Healing occurred within 90 days of the start of the study [18].

The following study investigated the use of a phage cocktail of MR-5 and MR-10 phages coated with transferrins (agents that allow improved transport, regulate drug release and penetration) to treat skin abscesses on the thighs of mice caused by MRSA. Its efficacy was then compared with a cocktail containing free phages without transferrins. In both cases, there was a significant reduction in bacterial load – the cocktail with transferrins resulted in a maximum load on day 1 of treatment, followed by a gradual decrease on day 6 when the tissue was completely sterile. For the free phage cocktails, the maximum load was observed on day 3 of treatment, and on day 9 the tissue was sterile. Without treatment, the infection resolved itself after 15 to 20 days [7].

Skin infections on the ears of rabbits colonized with S. aureus strain associated with biofilm formation were treated with bacteriophage every other day. The second control group was not treated at all, and in the third group the infected tissue was removed in addition to phage treatment. While in the first two groups there was no significant reduction in the number of bacteria and no acceleration of healing, in the third control group there was an improvement in all observed parameters [8].

Even a single application of phage had the same therapeutic effect on the treatment of chronic diabetic wounds as the drug (an antibiotic from the oxazolidinone group) used to treat diabetic ulcers. When the two treatments were combined, the resulting treatment was much faster and more successful (in terms of histopathological analysis, bacterial load detected and wound size) [9].

The first article in France describing successful phage therapy for S .aureus dates back to 1921. Research was carried out by Bruynoghe and Maisin in Belgium in the same year. It was found that injection of staphylococcal phages near ulcers (furuncles and carbuncles) resulted in improvement in 6 patients within 48 hours. There was a reduction in swelling, a reduction in pain and a reduction in fever [14].

Phage therapy for recurrent farunculosis and impetigo was also considered by Gougerot and Peyre. The phages were injected by syringe into the affected area, in the case of impetigo, first the crusts were removed from the wounds and then the wounds were swabbed with phage. A poultice saturated in phage solution was then applied to the wound. During the first day there was an enlargement of the pustules, but after 48 hours the lesions dried up and disappeared [14].

Already during the Winter War of the USSR against Finland in 1939-1940, phage preparation was used to treat infections of various types of wounds. Soldiers were treated with a phage cocktail effective against bacteria of the Streptococcus and Staphylococcus genera developed at the Eliav Institute in Tbillisi in present-day Georgia. Thanks to the phage therapy, up to 89% of the wounded soldiers survived, compared to 58% of those who did not undergo phage therapy. The incidence of gangrene in soldiers was also reduced by 30% [10].

In Poland, Sklopek et al. applied phage therapy to 550 patients suffering from purulent skin infections (suppurative ulcers, subcutaneous inflammation, furunculosis, inflammation of lymphatic ducts…) between 1981 and 1986. Over 92.4% of the patients (508) responded positively to treatment, 38 patients experienced temporary improvement and 4 patients were not treated effectively. A total of 518 patients were affected by antibiotic-resistant infections [15]. In another Polish study involving 1307 patients affected by multidrug-resistant infections, phage therapy of suppurative burns was described in 49 patients. Phages were administered both topically and orally. Forty-two patients were successfully cured. The average duration of treatment was 32 days [21].

Over-the-counter phage products are available in Georgia and Russia. Pyophage is a cocktail of phages against several different species of bacteria, including S. aureus. It is used to treat purulent skin or wound infections [14].

In the book by Chanishvilio and Sharp, the chapter Phage Therapy in Dermatology describes successful phage therapy for a wide range of skin infections – abscesses, furuncles and various dermatitis. Over 6000 patients were enrolled in the study and 70-100% of patients recovered within 4-8 days of starting treatment. The phages were injected every other day with the dose gradually increasing. After only 2 injections, it brought significant pain relief, and the resulting scarring of the healed wound was significantly less. Another successful Georgian study in 1970 dealt with the treatment of staphylococcal ulcers, carbuncles, furuncles and hidradenitis where antibiotics had failed. 94.4% of patients were successfully cured, 4.3% showed significant improvement and 1.3% did not respond to treatment [14].

Nowadays, clinical trials are only conducted when all known treatments have been exhausted. One such study was conducted on 6 diabetic patients whose ulcers were infected with MRSA and the infection was not sensitive to any antibiotic treatment. The ulcers were treated with Sb-1 phage and there was complete eradication of MRSA from the wounds in all patients in the study. After 7 weeks, the ulcers healed completely [11].

Cislo et al. conducted a study on phage therapy of purulent skin infections caused by various pathogens (E.coli, S. aureus, K. pneumoniae, P. aeruginosa…) in 31 patients. During 2-16 weeks of treatment, the general condition improved, local inflammation was suppressed, ulcers healed faster and control bacteriological tests were negative. Complete healing occurred in 16 patients, significant improvement in 7, only temporary improvement in 2, and inadequate improvement in 1. Adverse effects occurred in 6 cases [19].

PhagoBioDerm has been used to heal radiation burns infected with MRSA. PhageBiDerm is a cocktail of lytic phages with different hosts in a polymeric mixture. Wound suppuration, which lasted for more than a month despite aggressive antibiotic treatment, successfully resolved after 2-7 days from the first treatment [12]. Markoishvili and his colleagues also used PhagoBioDerm to treat infected skin ulcers of venous stasis. The product was administered both alone and in combination with other treatment strategies. Complete healing of the ulcers occurred in 70% of 100 patients [14].

In addition to the phages themselves, endolysins – lytic proteins that are used to get the phages out of the host cell. These are highly specific to the host and have no effect on the human organism and the surrounding microflora. Micreos has introduced the Gladskin brand, whose main active ingredient is phage endolysins. One of these products is Staphefekt SA.100, which has been found to significantly reduce bacterial load and treat skin infections caused by S. aureus when applied topically to the affected area [13].

References:

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