Phage therapy: the forgotten therapy in Brazil

The world knows little about the therapeutic use of bacteriophages in South America. To remedy this situation, The Lancet published a comprehensive overview of the history of phage therapy in Brazil, whose heyday was the “golden age” of bacteriophages worldwide – the 1920s. The advent of antibiotics led the Western world to forget phages in the long term, but due to the spread of antibiotic resistance, interest in them has resurfaced in the last 20 years.

The heyday of phage therapy in Brazil is closely linked to the name of Dr. José da Costa Cruz and the Oswaldo Cruz Institute, an important center for biomedical research in Rio de Janeiro, then the capital of the Brazilian Republic.

The first scientific publication mentioning bacteriophages appeared in 1921, and two years later, the results of experiments on the clinical application of oral phage drugs for bacillary dysentery (shigellosis) were published. Throughout the year, Cruz and his colleagues continued testing, and by 1924, the institute had already produced 10,000 vials of phage preparations against dysentery and distributed them to Brazilian doctors. Positive feedback and reports on the effectiveness of bacteriophage treatment for dysentery began to arrive from various cities. Doctors wrote that with the application of the phage preparation, symptoms disappeared within a few hours, and recovery occurred after 2 days. Bacteriophages were widely used in the treatment of dysentery among soldiers involved in suppressing the revolutions in Sao Paulo in 1924. After such field trials,

By 1923, phage therapy was already known to the Brazilian medical community. Notably, at that time, another phage therapy enthusiast, Nelson Barbosa, described three cases of phage treatment for staphylococcal infections. In 1924, several articles on phage therapy were presented at a meeting of the Society of Medicine and Surgery in Rio de Janeiro. The first speaker considered whether phages are living organisms. The second shared experiences of the therapeutic use of bacteriophages, including the successful treatment of dysentery mentioned above. The third speaker commented on the immune response to phage injection, the problems of isolating the pathogen and selecting phages, and presented the results of a series of laboratory and clinical cases.

In 1929, at the South American Conference on Hygiene, Microbiology, and Pathology in Rio de Janeiro, Cruz presented an overview of the global application of phage therapy and explained the experiences with phage use in Brazil. He mentioned his own failed attempt to treat bacteremia in patients with typhoid and paratyphoid, as well as a failure in treating cholera because he had not isolated a specific phage. Professor Oscar Pereira from Porto Alegre spoke about his own experiences in phage therapy for dysentery. He noted that phage therapy could significantly reduce mortality in patients with severe dysentery, achieve complete clearance of pathogenic bacteria, and prevent bacterial carriers. Pereira also shared his experiences in effective phage therapy for urinary tract infections with Escherichia coli, as well as 9 cases of pyoderma and 32 cases of Staphylococcus-induced furunculosis.

At that time, phage therapy was included as a separate section in the training course offered to Brazilian doctors by the Oswaldo Cruz Institute.

In 1934, Cruz and colleagues sent a message to the Brazilian National Academy of Medicine, stating that phage therapy for staphylococcal infections was not as well-deserved as a case of a young patient suffering from staphylococcal septicemia and furunculosis for months, until he received 6 injections adapted for his phage pathogen and topical abscess treatment.

In 1935, publications on the use of bacteriophages continued to appear in Brazil. For example, the successful treatment of staphylococcal furunculosis with bacteriophages in a child was described; two cases of pyelitis in children caused by E. coli; and osteomyelitis. Commercially available bacteriophages were used for treatment.

In 1938, Cruz published a review describing the treatment of 33 patients with septicemia caused by gonococci (1 patient), streptococci (14), staphylococci (12), and Escherichia coli (6). Notably, Cruz stated that phage project injection was the most effective treatment for staphylococcal infections. In the review, he provided some interesting facts about the practice of phage therapy in Brazil. Yes, bacterial infections were not always attempted for phage treatment, even when specific phages were available. Furthermore, phage therapy required the consent of the patient or their relatives.

In 1939, a review of phages was dedicated to his colleague Genesio Pacheco, Cruz. He criticized commercial preparations of bacteriophages produced by private mass companies. He claimed that manufacturers, for profit reasons, did not meet all technical requirements, leading to poor quality phage products. In his opinion, however, phage production should not be commercially available, as it is no less important than legal disputes, culture, or education. It is worth noting that one of the discoverers of bacteriophages, the French researcher Felix d’Hérelle, also opposed the commercialization of bacteriophage production.

In 1940, Cruz published a review describing his own involvement in two Brazilian clinical trials of phage therapy for typhoid fever. The results of both tests were negative. At the same time, he was a passionate advocate for the treatment of purulent phage infections – from skin to septicemia – but emphasized that therapeutic phages should be adapted to pathogens isolated from the patient. Dr. Jose da Costa Cruz died in 1940.

In 1944, a review on the use of phages in staphylococcal infections in Brazil was published, describing the good results of phage therapy in such patients. The author noted that bacteriophages are often used when other methods have already proven to be ineffective, even in recurrent infections. He reported positive results of oral phage application in the treatment of boils and acne. He also reported that cases of bacterial resistance to phages are rare.

In the first half of the 1940s, there was a multitude of publications on various methods of antibacterial therapy. For example, in an article on the treatment of staphylococcal meningitis, the authors suggested using phages in combination with sulfonamides and antitoxic serum for the first week, and then only phages. Gradually, however, antimicrobial chemotherapy, particularly penicillin, came to the forefront. In general, interest in phage therapy continued in the 1940s but waned due to the proliferation of sulfonamides and penicillin, as well as several unsuccessful clinical trials of phage preparations.

Phage therapy was not officially banned or restricted, but merely displaced by the wave of penicillin’s popularity. The generation of specialists changed, and young Brazilian doctors were convinced that phage therapy was a thing of the past and that antibiotics were the future. The decline in phage popularity was also linked to the large number of substandard drugs that flooded the Brazilian market (we mentioned the problem above). This situation was observed in most countries worldwide. Only in the USSR and Poland did the research and testing of phage preparations continue.

Over the decades, antibiotics truly revolutionized medicine and influenced all industries. However, they gradually lost effectiveness as resistant bacteria spread. And then, humanity remembered bacteriophages again.

In the history of bacteriophage use in Brazil, there are many gaps: the origin of many phages, methods for their purification, and drug manufacturing. However, it is known that Brazilians have done many important things in this field. In particular, Dr. Jose da Costa Cruz and his colleagues successfully treated bacillary dysentery (shigellosis) and staphylococcal infections. In the first case, they practiced oral administration of specific phages; in the second, oral and topical injection. These infections still remain a major problem for humanity. Shigella causes almost 200 million cases of dysentery each year and is the world’s second most common cause of gastrointestinal infections. Staphylococci influence the spread of antibiotic-resistant strains. Therefore, the return of phages to clinical practice seems quite logical.

machine translation of the source:

* References to the original sources of the above-mentioned studies and a description of a number of clinical cases of phage therapy in Brazil can be found here: de Freitas Almeida GM, Sundberg LR. The forgotten history of Brazilian phage therapy. The Lancet, published March 23, 2020. DOI: https://doi.org/10.1016/S1473-3099(20)30060-8