Little is known about the therapeutic use of bacteriophages in South America. To address this, The Lancet published a comprehensive review devoted to the history of phage therapy in Brazil, which flourished during the 1920s, the "golden age" of bacteriophages worldwide. The advent of antibiotics led to a long period of neglect of phages in the Western world, but the spread of antibiotic resistance has led to renewed interest in bacterial viruses in the past 20 years.

The rise 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 medical and biological research located in Rio de Janeiro, the then capital of the Brazilian Republic.

The first scientific publication mentioning bacteriophages appeared in Brazil in 1921, and two years later, the results of experiments on the clinical use of oral phage preparations for bacillary dysentery (shigellosis) were published. Cruz and his colleagues continued their trials for a year, and by 1924, the Institute had produced and distributed 10,000 vials of the anti-dysentery phage preparation to Brazilian doctors. Positive reviews and reports of the effectiveness of treating dysentery with bacteriophages began to arrive from various cities. Doctors wrote that with the use of the phage preparation, symptoms disappeared within a few hours, and recovery occurred within two days. Bacteriophages, in particular, were widely used to treat dysentery in soldiers recruited to suppress the revolution in São Paulo in 1924. Following these field trials—indeed, the first such large-scale phage therapy trial in the world—the Oswaldo Cruz Institute officially recommended the use of phages for bacillary dysentery and began providing a phage preparation, called Bacteriofagina disenterica, upon request.

By 1923, phage therapy was already well known in the Brazilian medical community. At that time, Nelson Barbosa, another phage therapy enthusiast, described three cases of treating staphylococcal infections with phages. In 1924, several papers on phage therapy were presented at a meeting of the Rio de Janeiro Society of Medicine and Surgery. The first speaker examined the question of whether phages are living organisms. The second shared his experience with the therapeutic use of bacteriophages, including a detailed account of the aforementioned successful treatment of dysentery. The third speaker shared his views on the immune response to phage injection, the problems of isolating the causative bacteria, and phage selection, and also presented the results of several laboratory experiments and clinical cases.

In 1929, at the South American Conference on Hygiene, Microbiology, and Pathology held in Rio de Janeiro, Cruz presented an overview of the use of phage therapy worldwide and also discussed in more detail the experience of using phages in Brazil. He recounted his unsuccessful attempt to treat bacteremia in patients with typhoid and paratyphoid fever, as well as his failure to treat cholera due to his failure to isolate a specific phage. At the same conference, Professor Oscar Pereira of Porto Alegre shared his experience with phage therapy for dysentery. He noted that phage therapy had significantly reduced mortality among patients with severe dysentery, as well as completely eradicated pathogenic bacteria and prevented bacterial carriage. Pereira also shared his experience of effective phage therapy for urinary tract infection caused by Escherichia coli , as well as 9 cases of pyoderma and 32 cases of furunculosis caused by staphylococcus.

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

In 1934, Cruz and his colleagues submitted a report to the Brazilian National Academy of Medicine noting that phage therapy for staphylococcal infections was not prescribed as often as it should be, and also cited the case of a young patient who, following furunculosis, suffered from staphylococcal septicemia and was unsuccessfully treated for a month until he received six injections of phages adapted to his pathogen in combination with local phage therapy for the abscess.

In 1935, publications on the use of bacteriophages continued to appear in Brazil. For example, successful treatment with bacteriophages was described for staphylococcal furunculosis in a child; two cases of pyelitis in children caused by E. coli; and osteomyelitis. Commercially produced bacteriophages were used for this 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). Cruz concluded that injections of phage preparations were the most effective available treatment for staphylococcal infections. In his review, he provided interesting facts about the practice of phage therapy in Brazil. For example, bacterial infections were not always treated with phages, even when specific phages were available. Furthermore, phage therapy required the consent of the patient or their relatives.

In 1939, Cruz's colleague Genesio Pacheco reviewed phages. He criticized commercial bacteriophage preparations, which were mass-produced by private companies. He argued that, for profit, manufacturers failed to adhere to all technical requirements, resulting in poor-quality phage preparations. He believed that phage production should not be commercialized, as it was no less important than legal proceedings, culture, or education. It's worth remembering that one of the discoverers of bacteriophages, the French researcher Félix d'Hérelle, also opposed the commercialization of bacteriophage production.

In 1940, Cruz published a review describing his participation in two Brazilian clinical trials of phage therapy for typhoid fever. The results of both trials were negative. At the same time, Cruz ardently advocated phage treatment for purulent infections—from skin diseases to septicemia—but emphasized that therapeutic phages must be adapted to the pathogen strains isolated from the patient. Dr. José da Costa Cruz died in 1940.

In 1944, a review of the use of phages for staphylococcal infections in Brazil was published, describing the positive results of phage therapy in such patients. The author noted that bacteriophages are often used when other treatments have failed, including in cases of recurrent infections. He described the positive results of oral phage administration in the treatment of furunculosis and acne. He also reported that bacterial resistance to phages is rare.

The first half of the 1940s saw a surge in publications devoted to various antibacterial therapy methods. For example, in an article on the treatment of staphylococcal meningitis, the authors proposed using phages in combination with sulfonamides and antitoxic serum for a week at the beginning of treatment, followed by phages alone. However, antimicrobial agents, primarily penicillin, gradually came to the fore. Overall, interest in phage therapy persisted throughout the 1940s, but gradually waned due to the widespread use of sulfonamides and penicillin. Several unsuccessful clinical trials of phage preparations also played a role.

Phage therapy wasn't officially banned or restricted; it was simply supplanted by the rise of penicillin. A generation of specialists had passed, 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 due to the large number of low-quality drugs flooding the Brazilian market (we mentioned this problem above). This situation was observed in most countries around the world. Only in the USSR and Poland did phage research and testing continue.

Decades passed, and antibiotics truly revolutionized medicine, but they gradually began to lose their effectiveness due to the spread of resistant bacteria. Then humanity once again turned to bacteriophages.

The history of bacteriophage use in Brazil remains a mystery: the origins of many phages, their purification methods, and preparation are unknown. However, it is known that Brazilians made significant contributions in this field. In particular, Dr. José da Costa Cruz and his colleagues successfully treated bacillary dysentery (shigellosis) and staphylococcal infections. In the former case, they used oral administration of specific phages, while in the latter case, they used injections, oral administration, and topical application. These infections remain a huge problem for humanity. Shigella causes nearly 200 million cases of dysentery annually and is the second-leading cause of death related to gastrointestinal infections worldwide. Staphylococci are associated with the spread of antibiotic-resistant strains. Therefore, the return of phages to clinical practice seems entirely logical.

* Links to the original sources of the studies mentioned, as well as descriptions of several clinical cases of phage therapy in Brazil, can be found here: de Freitas Almeida GM, Sundberg LR. The forgotten tale of Brazilian phage therapy. The Lancet, Published: March 23, 2020. DOI: https://doi.org/10.1016/S1473-3099(20)30060-8