“The Treatment of Early Syphilis with Penicillin: A Preliminary Report of 1418 Cases” (1944), by Joseph Earle Moore, J. F. Mahoney, Walter Schwartz, Thomas Sternberg, and W. Barry Wood

In 1944, Joseph Earl Moore and colleagues published “The Treatment of Early Syphilis with Penicillin: A Preliminary Report of 1418 Cases,” hereafter “Treatment of Early Syphilis,” in the Journal of the American Medical Association. Moore and colleagues’ article was one of the first to study and explore the use of penicillin, an antibiotic that can kill bacteria, as a treatment for humans with syphilis, which is a bacterial disease that spreads through sexual contact. In its early stages, syphilis can cause rashes and genital sores, but in its late stages, it can also lead to organ damage. In “Treatment of Early Syphilis,” Moore and his colleagues explain that they conducted a study to determine the effects and optimal dose of penicillin in humans with early syphilis. The authors found that giving individuals with syphilis specific doses of penicillin can heal their syphilitic lesions and eradicate the bacterium that causes syphilis from their bodies. “Treatment of Early Syphilis” was one of the first articles to demonstrate that syphilis, specifically early syphilis, could be effectively treated with penicillin, the drug that physicians still most commonly use as of 2024 to treat the sexually transmitted disease.

1. Background and Context
2. Article Roadmap
3. Detailed Content
4. Impact

Background and Context

The authors of “Treatment of Early Syphilis” were part of the Penicillin Panel, a group of physicians, scientists, and army officials tasked with exploring the effects of penicillin treatment on individuals with syphilis. At the time of writing, Moore was a physician based in Baltimore, Maryland, and was a part of the Venereal Disease Division of the Medical Clinic at Johns Hopkins Hospital in Baltimore. John Friend Mahoney was the medical director of the United States Public Health Service in New York City, New York, and Walter Schwartz was a commander in the United States Navy. Thomas Sternberg was the lieutenant colonel of the Medical Corps of the Army of the United States. Finally, William Barry Wood was a physician based at Washington University in St. Louis, Missouri, and he later became a professor of microbiology at Johns Hopkins University in the 1950s.

Historical records of syphilis date back to the 1400s, and though it was known as the French disease in the late fifteenth century, many scholars argue that syphilis originated in North America in the late fifteenth and early sixteenth centuries. Syphilis spread to Europe around that time, covering people’s bodies in painful lesions and infecting and killing millions of individuals. One theory for that spread is the Columbian hypothesis, which states that the native populations of the Americas passed the disease on to the Europeans who took it home with them after Columbus’s voyage. However, a 2020 study published in the journal Current Biology reports that there is some evidence that the bacterium that causes syphilis was already present in Europe at that time. The disease remained a problem over the following centuries. Syphilis’s ability to spread quickly forced the implementation of legislation that controlled the spread, such as England’s Contagious Disease Act in the twentieth century, which attempted to control prostitution in England to reduce the spread of sexually transmitted diseases, such as syphilis, in the general population and the military. Throughout those centuries, physicians in Europe and the US diagnosed syphilis primarily by observation of symptoms, including rashes, boils, and lesions, but that method of diagnosis was not very specific and accurate. Finally, in 1905, Erich Hoffman, who studied dermatology, or the branch of medicine concerned with diseases of the skin, and Fritz Schaudinn, who studied animal behavior and sexually transmitted diseases, discovered the causative agent of syphilis to be the bacterium Treponema pallidum.

However, even after the discovery of the cause of syphilis, physicians still had no effective method of treating the disease until researchers developed drug therapies, such as Salvarsan and penicillin. In 1910, Paul Ehrlich, a physician and medical researcher from Germany, developed Salvarsan, which was a chemical-based therapy that became the preferred treatment for syphilis. Although Salvarsan was one of the first effective drug treatments for syphilis, it was also toxic. Despite its disadvantages, Salvarsan remained the treatment of choice for syphilis through the 1930s. In 1928, Alexander Fleming, a physician who studied bacteria in Scotland, discovered penicillin, one of the world’s first antibiotics, which would eventually be used to treat syphilis and other bacterial infections.

During World War II, syphilis rates were high in the US military, and by 1941, researchers had developed methods to purify and mass produce penicillin, so the government created the Penicillin Panel. In the late 1930s and early 1940s, Howard Florey, a physician and researcher who studied pharmacology, developed one of the first successful methods to reliably extract and purify penicillin. In 1941, Florey and his research team discovered a method to mass produce penicillin. Around the time Florey made advancements with penicillin, venereal diseases, or sexually transmitted diseases, such as syphilis, became increasingly prevalent in troops in the United States Army. According to a 1945 paper analyzing venereal diseases during World War II, forty-five percent of individuals in the first draft tested positive for syphilis during their medical examination. The government attempted to educate soldiers on the risks of sexually transmitted diseases and provide chemical treatments, but that did little to solve the problem. The military then created the Penicillin Panel to study the spread of the disease among soldiers and determine if penicillin could help curb it.

Prior to “Treatment of Early Syphilis,” coauthor Mahoney conducted a study that provided preliminary data indicating that penicillin could be effective at treating syphilis. In 1943, Mahoney and two of his colleagues demonstrated that penicillin could effectively treat syphilis in rabbit models as well as in four human patients with early syphilis. As a result of Mahoney’s observations and under the guidance of the Committee on Medical Research of the Office of Scientific Research and Development, a committee that oversaw research of interest to the US government, researchers established the Penicillin Panel to study the effectiveness of penicillin in treating individuals with syphilis. The Penicillin Panel was one of the first groups to test penicillin’s effect on a larger sample size of humans with syphilis.

Article Roadmap

Moore and his colleagues organize “Treatment of Early Syphilis” into five general parts. In the untitled introduction, the authors state that previous studies had already established penicillin’s ability to treat syphilis in animal models and in some humans, which motivated them to conduct a larger, multi-center study. In the untitled methods section, the authors explain that they used penicillin to treat individuals with syphilis in twenty-three research centers across the US. They report that they administered varying doses of penicillin to test the effect of the drug on the healing of syphilitic lesions and the concentration of the bacteria in patients’ blood. In the third section, titled “The Immediate Results of Treatment,” the authors established that penicillin effectively treated syphilis at all dosage levels, but that higher doses of what they called units of penicillin administered every three hours for 7.5 days was best at treating lesions and reducing concentrations of bacteria in patients’ bodies. Next, the authors report that penicillin was effective at treating patients with rare cases of syphilis, including those who were positive for syphilis in their cerebrospinal fluid, which is the fluid that runs through the brain and spinal cord, patients with inflammation of the nervous system organs due to syphilis, and infants who contracted the disease during pregnancy. However, the authors note that their study did not produce clear findings about whether penicillin could effectively treat syphilis in individuals who were pregnant. In the final section, titled “Summary,” the authors reiterate their findings and argue that penicillin is an effective treatment for syphilis.

Detailed Contents

In the first section, the researchers explain that Mahoney’s studies influenced the formation of the Penicillin Panel and provided the authors with a basic medical understanding of the effectiveness of penicillin treatment on syphilis. Mahoney analyzed the effect of penicillin on syphilis in rat models and four human patients. The researchers claim that they conducted their studies to advance scientific treatments for syphilis. They also explain that their results in “Treatment of Early Syphilis” demonstrate the effect of penicillin treatment on human beings. They state that the penicillin used in the study derived from government sources.

In the untitled methods section, the authors begin by outlining which institutions their subjects originated from and stating that all researchers must follow the Subcommittee of Venereal Diseases’ guidelines. The subjects came from twenty-three different research centers and clinics, including the US Army Medical Center located in Fort Bragg, North Carolina, the University of Pennsylvania Hospital in Philadelphia, Pennsylvania, and Johns Hopkins Hospital in Baltimore, among other institutions. The researchers state that the physicians and scientists at each of the clinics agreed to treat early syphilis patients with penicillin according to Moore’s assigned treatment schedule and to consolidate their results under the Subcommittee of Venereal Diseases, of which Moore and his colleagues were members. Next, the authors claim that they only recruited subjects who undoubtedly had early syphilis, as detected by the presence of Treponema pallidum, the bacteria that causes syphilis.

Next, the researchers further classify their subjects according to race, gender, and which of three types of syphilis they presented with. They state that 177 patients had seronegative primary syphilis, meaning that they had early syphilitic symptoms like genital sores but no Treponema pallidum in their blood. Some 379 patients had seropositive primary syphilis, meaning they had both early syphilis symptoms and Treponema pallidum in their blood. Some 765 patients had secondary syphilis, meaning their syphilis had progressed beyond symptoms of early syphilis, and those patients displayed symptoms such as muscle fatigue and rash. Ninety-seven patients had recurrent syphilis, meaning that they had contracted and recovered from syphilis previously, but the disease had since returned. The majority of patients were Caucasian and African American. As for biological sex, 791 subjects were male and 627 were female, of whom fifty-eight were pregnant at the time of treatment.

Then, the authors describe the treatment schedule for the four treatment groups of varying doses of penicillin and explain that their goal was to identify the ideal dose of penicillin to treat syphilis. Moore and his colleagues report that they standardized several factors across all their subjects. First, they ensured that all their subjects received penicillin intramuscularly, or through an injection into their muscles. However, they note that twenty-five of their subjects were initially part of a different study and received penicillin intravenously, or through the vein, rather than intramuscularly. The research group states that they also standardized treatment administration for all subjects. For every subject, the authors write that a physician administered penicillin treatments every three hours, and the length of the entire treatment regimen was 7.5 days. So, in total, each patient received sixty intramuscular injections. However, the researchers explain that the doses of penicillin administered for each subject varied by treatment group so that the researchers could assess which dose was most effective. Thus, one group received 60,000 units of penicillin over the course of their treatment regimen, while the other three groups received 300,000, 600,000, 1.2 million, and 2.4 million total units of penicillin, respectively.

The authors conclude the untitled methods section by cautioning readers of the preliminary nature of the results presented in “Treatment of Early Syphilis.” Specifically, they state that the majority of the results in the article were from data collected in the first two months of their study, and they explain that they evaluated only 113 of the 1,418 patients in this study over four months. While Moore and colleagues went on to publish results on the treatment of prenatal syphilis, or syphilis contracted while still a fetus in the uterus, and advanced, or late-stage, neurosyphilis, in future articles, they did not publish the three-month and six-month study results for “Treatment of Early Syphilis.”

In the following section titled “The Immediate Results of Treatment,” the researchers explain that penicillin could treat syphilis and alleviate symptoms in a large majority of their subjects. In the sub-section titled “Disappearance Time of Treponema pallidum from Open Lesions,” the researchers explain that based on results from approximately half of their subjects, regardless of the dose of penicillin each patient received, the bacteria disappeared from their lesions between six and sixty hours after the start of treatment. Additionally, when the researchers compared the group of participants who received the lowest total dose of 60,000 units with the group who received the highest total dose of 2.4 million units, average bacteria disappearance time only varied between twenty-one hours and fourteen hours, respectively. By comparing those results with the data from the twenty-five patients included in “Treatment of Early Syphilis” who received intravenous penicillin, the researchers concluded that intravenous injection held no advantage over intramuscular injection when it came to disappearance time of Treponema pallidum from syphilitic lesions. Thus, penicillin proved effective at reducing levels of bacteria in lesions regardless of dose level or method of injection.

In the following two subsections titled “Healing of Lesions” and “Serologic Response,” Moore and colleagues explain that lesion healing and serologic response demonstrated improved results with higher-dose treatments. In the sub-section titled “Healing of Lesions,” the authors state that all doses prompted healing of lesions to some degree, but that higher doses of penicillin seemed to heal lesions most effectively. The authors state that the treatment group receiving a total dose of 60,000 units of penicillin over 7.5 days of treatment healed lesions more slowly than with arsenical therapy, a type of chemical therapy that physicians used to treat syphilis at the time. However, at total doses of 300,000 units and higher, the research group explains that penicillin treatment matched, and even surpassed, the rates of lesion healing that syphilitic chemotherapies achieved over the same time span. Then, in the sub-section titled “Serologic Response,” Moore and colleagues state that they analyzed serologic response, or the antibody response of an individual, for all treatment groups. They explain that all dosage levels led to a decrease in the concentration of syphilis bacteria in patient serum, a component of blood, twenty days after the start of treatment and the general trend depicted that with a larger penicillin dose, there is a greater rate of decrease in bacteria concentration. Based on serologic response, the research group claims that penicillin yielded satisfactory results in 95.8 percent of seronegative primary syphilis patients.

In the following subsection, “Relapse After Penicillin Treatment,” the research team explains that they investigated the frequency of syphilis relapse to determine the minimum effective dose of penicillin for syphilis. They state that initially they were not able to determine the minimum effective dose of penicillin for syphilitic patients because all doses had similar effects on the disappearance of Treponema pallidum from open lesions, the healing of lesions, and serological reversal. Thus, to figure out the minimum effective dose, they write that they examined the frequency of syphilis relapse, or how commonly patients became reinfected with syphilis, among participants who received each dose. The researchers monitored relapse of syphilis in each of their treatment groups and found that generally, higher doses of penicillin led to lower rates of relapse, suggesting higher doses are more effective. Additionally, patients who received intravenous injections of penicillin relapsed at rates five to six times higher than other patients. Moore and his colleagues also found that regardless of dose received, incidence of relapse increased as disease severity increased, meaning patients who experienced later stages of syphilis were more likely to become reinfected regardless of penicillin treatment. Secondary syphilis patients had a relapse rate of ten percent while seronegative primary syphilis patients had a relapse rate of 3.2 percent. Though the researchers state that there was no correlation between the relapse time and dose, they do provide a range of time for relapse, between thirty-eight and 294 days after the start of treatment, acknowledging that there could be longer relapse times as well that were outside of their observation period.

In the sub-section titled “The Optimum Time-Dose Relationship for Penicillin in Early Syphilis,” the researchers conclude that total doses below 600,000 units of penicillin are ineffective and a combination treatment of penicillin with mapharsen, an arsenic-based drug, demonstrates success. They argue that no clear optimal dose can be drawn from seronegative primary syphilis data. However, any total dose below 600,000 units of penicillin over 7.5 days is ineffective for seropositive primary and early secondary syphilis. The researchers also explain that utilizing 60,000- and 300,000-unit doses in combination with the known curative dose of mapharsen, 320 mg, reduced relapse rates, as only one patient out of ninety-four experienced a relapse of syphilis in thirty-eight days or more. That suggests that any dose of penicillin in combination with mapharsen is effective at resolving syphilis symptoms.

In the following five subsections, the researchers report that penicillin proved effective at treating syphilis in patients with five rare cases of the disease. For example, in “Results of Treatment of Special forms of Early Syphilis,” they describe that in ten of thirteen patients positive for Treponema pallidum in their cerebrospinal fluid, the fluid abnormalities improved or resolved after penicillin treatment. In “Acute Syphilitic Meningitis,” the authors describe that ten patients with that case type received successful treatment and symptomatic relief with a total dose of 1.2 million units. In “Treatment Resistant Early Syphilis,” they describe how eight patients who were resistant to traditional syphilitic chemotherapies all saw improvement in symptoms after penicillin treatment. In “Infantile Congenital Syphilis,” Moore and colleagues note that twenty infants born with congenital syphilis saw significant improvements with doses of 20,000 unit per kilogram of body weight. Finally, in “The Outcome of Pregnancy,” they specify that they successfully treated all fifty-eight pregnant women infected with syphilis with penicillin treatment. However, fetal status was unknown at the time of the article’s publication.

At the end of “Relapse After Penicillin Treatment” and in the following section, “Reactions to Penicillin,” the authors consider any negative reactions to penicillin itself and evaluate the limitations to their study. They admit that some patients experienced symptoms such as rash and fever, but none were severe enough to stop treatment. They report that fifty-nine percent of patients experienced symptoms such as mild fever, chills, and rash within the first twenty-four hours after treatment began. Fifty-nine additional patients also experienced other reactions, including skin rashes, mild gastrointestinal disturbances, or buttock lesions. The researchers also state that they expected that some patients will likely be resistant to penicillin, as five to fifteen percent of patients were resistant to arsenic, bismuth, and other traditional chemotherapies for syphilis at the time. Thus, they propose a combination of penicillin and chemotherapy to best treat syphilis and prevent reinfection. Finally, Moore and his colleagues caution that their dosage schedule required hospitalization and constant monitoring, something for which facilities at the time were not equipped. They suggest exploring the effectiveness of total doses of larger than 1.2 million units in four- and eight-day intervals in future studies. They also suggest varying the time interval between doses, further comparing intravenous and intramuscular administration of penicillin, and establishing the efficacy of penicillin combined with arsenic and bismuth therapies.

In the final section, titled “Summary,” the research group argues that their preliminary results show that penicillin is effective at healing lesions and clearing syphilis from the blood. They state that all total doses from 60,000 to 1.2 million total units of penicillin administered intramuscularly over the course of the 7.5-day treatment regimen caused a decrease in patients’ syphilitic symptoms. However, the researchers note that the higher the dose administered, the more beneficial the penicillin treatment. They emphasize that those results were the same for patients treated with penicillin intramuscularly versus intravenously, except patients treated intramuscularly experienced relapse at lower rates. However, Moore and his colleagues highlight that the lowest rate of relapse occurred in patients treated with a combination of penicillin and mapharsen, which the authors suggest may be the best combination of treatments. Still, penicillin treatment was effective in primary and secondary syphilis patients, as well as in patients who were resistant to chemotherapy treatment or with special cases of syphilis. Finally, the authors note that a total dose of penicillin lower than 1.2 million units should not be used to limit relapse rate and maximize treatment effectiveness, especially for patients with secondary syphilis.

Impact

As of 2024, “Treatment of Early Syphilis” has been cited ninety times, according to Google Scholar. Following the publication of the article, in 1944, the pharmaceutical company Pfizer opened the first large-scale penicillin factory, allowing for the distribution of penicillin throughout the Allied Forces. That same year, penicillin became the primary treatment for syphilis in the armed forces of Britain and the US. By 1945, the US produced 6.8 trillion units of penicillin, and the drug also became widely accessible to the public. In 1945, penicillin received approval from the US Food and Drug Administration, and it became available at local pharmacies. In 1946, Norman Ingraham, a researcher at the Department of Pediatrics at the University of Pennsylvania in Philadelphia, and colleagues published an article citing “Treatment of Early Syphilis.” That article continued the efforts of Moore and his colleagues by demonstrating that penicillin administration to pregnant patients prevented the transmission of the disease to their fetuses. Also in 1946, Maxwell Kolodny, a member of the US Army Medical Corps, and colleagues referenced “Treatment of Early Syphilis” in their article that further characterized the adverse reactions of penicillin treatment, specifically skin rashes. In the 1930s, approximately one out of ten Americans, in a population of roughly 123 million, had syphilis. In 2022, there were over 207,000 syphilis cases in a total US population of 333 million individuals. However, as of 2024, rates are slowly increasing due to lack of implementation of protection against sexually transmitted diseases. As of 2024, a modified version of penicillin called benzathine penicillin G is the established treatment for syphilis. That variant of penicillin can cure early and secondary syphilis with one intramuscular injection.

“Treatment of Early Syphilis” was one of the first articles to demonstrate penicillin’s ability to treat syphilis in a large sample of human patients, which led to the widespread implementation of penicillin as a treatment for syphilis. The establishment of penicillin as a treatment for syphilis helped drastically reduce the prevalence of the sexually transmitted disease across the world.