Case Report : Effectiveness of benzathine penicillin in late latent syphilis: A Case Series

Agenda : 6th Case Report

Day/date : Thursday/ 18th February 2021
Moderator : Dr. dr. Satya Wydya Yenny, Sp.KK(K), FINSDV, FAADV
Counsellor : Dr. dr. Qaira Anum, Sp.KK(K), FINSDV, FAADV
Counsultant : dr. Tutty Ariani, Sp.DV
dr. Yosse Rizal, Sp.KK, FINSDV
Opponent : dr. Herkamela, dr. Resya I Noer

Miranda Ashar
Resident of Dermatology and Venereology Department
Medical Faculty of UNAND / Dr. M.Djamil Hospital Padang

Effectiveness of Benzathine Penicillin in Late Latent Syphilis: A Case Series

Abstract
Background: Syphilis is a systemic disease caused by Treponema pallidum. The disease has been
divided into primary, secondary, latent syphilis (early latent or late latent syphilis), and tertiary. Latent
syphilis was asymptomatic and it can be detected by serologic testing. The main therapy in late latent
syphilis is injection of benzatine penicillin G. Efficacy with this therapy is needed to be able to
prevent the progression of the disease becoming tertiary syphilis.
Case: We reported three cases of late latent syphilis. The first patient was a 31 years old man, the
chief complaint of patient was screened for sexually transmitted infections disease because his wife
diagnosed with genital condyloma acuminata and gonorrhea cervicitis. The results of VDRL was 1:32
and TPHA was 1:640. The second patient was a 34 years old man and the third patient wa a 53 years
old man. Their chief complaint were patients know the results of syphilis serology was reactive when
the patient donates blood. The second and third patients had a history of sex with women other than
their wives, while the third patient never had sex other than his wife. The results of VDRL in second
patient and third patient were 1:4 and 1:8, while the results of TPHA was 1:80 and 1:640. All cases
were treated with intramuscular injection of benzatine penicillin G 7.2 million units total,
administered as 3 doses of 2.4 million units intramuscularly each at one-week intervals. The results of
treatment were three cases got decrease VDRL titer.
Discussion: Serologic followup is important to monitor response to treatment late latent syphilis.
Treatment success is generally defined as a fourfold decline in serologic nontreponemal titer.
Although clinical experience supports the effectiveness of penicillin in achieving this goal, limited
evidence is available to guide choice of specific regimens or duration.
Key words: late latent syphilis, benzatin penicillin G, therapeutic response

Abstrak
Latar belakang:Sifilis merupakan penyakit sistemik yang disebabkan Treponema pallidum. Penyakit
ini dibagi menjadi primer, sekunder, sifilis laten (sifilis laten awal dan laten lanjut), dan tersier. Sifilis
laten tidak memiliki gejala dan dapat dideteksi dengan pemeriksaan serologis. Terapi utama sifilis
laten lanjut yaitu injeksi benzatin penisilin G intramuscular. Kesembuhan dengan terapi ini diperlukan
untuk mencegah perkembangan penyakit menjadi sifilis tersier.
Kasus: Kami melaporkan 3 kasus sifilis laten lanjut. Pasien pertama yaitu seorang laki-laki berusia 31
tahun. Keluhan utama pasien adalah pasien skrining untuk penyakit infeksi menular seksual karena
istrinya didiagnosa kondiloma akuminata genital dan servisitis gonore. Hasil pemeriksaan VDRL 1:32
dan TPHA 1:640. Pasien kedua yaitu seorang laki-laki berusia 34 tahun dan pasien ketiga yaitu
seorang laki-laki berusia 53 tahun. Keluhan utama kedua pasien adalah pasien mengetahui hasil
pemeriksaan serologi sifilis reaktif ketika pasien mendonorkan darah. Pasien pertama dan kedua
memiliki riwayat berhubungan seksual dengan perempuan selain istrinya, sedangkan pasien ketiga
tidak memiliki riwayat berhubungan seksual selain istrinya. Hasil VDRL pasien kedua dan ketiga

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yaitu 1:4 dan 1:8, sedangkan hasil TPHA yaitu 1:80 dan 1:640. Semua kasus diobati dengan injeksi
benzatin penisilin G dengan total dosis 7,2 juta unit, dibagi menjadi 3 dosis yang masing-masingnya
2,4 juta unit dengan interval 1 minggu. Hasil pengobatan pada dua kasus terdapat penurunan titer
VDRL dan satu kasus tidak terjadi penurunan titer.
Diskusi: Followup serologi penting untuk memonitor respon pengobatan pada sifilis laten lanjut.
Keberhasilan pengobatan biasanya terlihat dari penurunan titer serologi nontreponemal sebanyak 4
kali. Meskipun pengalaman klinis mendukung efektivitas penisilin dalam mencapai tujuan ini, bukti
yang tersedia terbatas untuk memandu pilihan regimen atau durasi pengobatan.
Kata Kunci: sifilis laten lanjut, benzatin penisilin G, respon terapi

INTRODUCTION
Syphilis is a systemic disease caused by Treponema pallidum. The disease has been
divided into stages based on clinical findings, helping to guide treatment and follow-up.
Persons who have syphilis might seek treatment for signs or symptoms of primary syphilis
infection (ulcers or chancre at the infection site), secondary syphilis (manifestations that
include skin rash, mucocutaneous lesions, and lymphadenopathy), or tertiary syphilis
(cardiac, gummatous lesions, tabes dorsalis, and general paresis). Latent infections (those
lacking clinical manifestations) are detected by serologic testing. Latent syphilis acquired
within the preceding year is referred to as early latent syphilis; all other cases of latent
syphilis are late latent syphilis or syphilis of unknown duration.1
According to the WHO estimate, there were 36.4 million cases of syphilis globally in
adults aged between 15 and 49 years in 2008. In the United Kingdom, the newly diagnosed
cases of syphilis increased from 2,650 in 2010 to 2,915 in 2011 and 75% of the cases
occurred in men who have sex with men (MSM). 2 Syphilis incidence in the United States has
been increasing steadily since 2001, the rate of primary and secondary syphilis was 6.3 cases
per 100,000 population in 2014. The current syphilis epidemic in the United States has been
primarily driven by increasing cases among gay, bisexual, and other men who have sex with
men (MSM). During 2013-2014, the primary and secondary syphilis rate increased 14.4% in
men and 22.7% in women.3
Latent syphilis was persons with historical or serological evidence for syphilis who
have never received treatment for this disease and who have no clinical manifestations. The
diagnosis of latency formally requires examination of the CSF to rule out asymptomatic
neurosyphilis, although most clinicians do not do a lumbar puncture in every patient with
probable latent syphilis. Latency has been somewhat arbitrarily divided into early latency and
late latency, on the basis of the time when untreated individuals are likely to have
spontaneous mucocutaneous (infectious) relapses. In the Oslo study of untreated syphilis at
the turn of the twentieth century, secondary relapses occurred in 25% of patients whose

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infection had become latent, with most relapses occurring in the first year. The U.S. Public
Health Service therefore defines early (potentially infectious) latency as 1 year from onset of
infection.4
Benzathine penicillin G, administered parenterally, is the preferred drug for treating
persons in all stages of syphilis. The preparation used (benzathine, aqueous procaine, or
aqueous crystalline), dosage, and length of treatment depend on the stage and clinical
manifestations of the disease. Treatment for late latent syphilis and tertiary syphilis require a
longer duration of therapy, because organisms theoretically might be dividing more slowly
(the validity of this rationale has not been assessed). Longer treatment duration is required for
persons with latent syphilis of unknown duration to ensure that those who did not acquire
syphilis within the preceding year are adequately treated.4
The response of latent syphilis to therapy is difficult to assess. Since the patient is free
of symptoms, the only possible response, barring the appearance of symptomatic tertiary
syphilis, is a change in serologic test results. The RPR titer often remains unchanged (serofast
state), or it may decline, but it usually does not return to negative. Rising titers suggest
therapeutic failure, in which case a CSF examination must be done and the patient must
receive either a repeat of the initial therapy or a more aggressive therapy, as for instance
intravenous penicillin for neurosyphilis.4
This case series reports the therapeutic response of benzathine penicillin in late latent
syphilis patients.

CASE REPORT
Case 1
We reported a 31 years old man that lived in Solok, came to outpatient clinic of
Dermatology and Venereology Dr. M. Djamil Hospital on December 30 th 2019 with chief
complaint patient was screened for sexually transmitted infections disease because the
patient's wife was diagnosed with genital condyloma acuminata and gonorrhea cervicitis. The
patient had a history of having sex with his girlfriend 12 years ago. The patient had 15
girlfriends and had sex sometimes using a condom and sometimes not using a condom.
Patient had sexual contact with his girlfriend in genito-genital and oro-genital. Patient never
had sex with men. The history of sexual partners experiencing genital ulcer, reddish patches
on both of palms and soles, white or gray patches on the armpits and groin, painful urination,
yellowish-whitish discharge, genital warts were denied. Since marriage, the patient has never
had sex other than his wife. Patient denied of having reddish patches on both of palms and
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soles. He also denied having ulcer that didn’t painful and vesicles on his genital. There was
no history of got transfusion, tatoo and injecting any ilegal drugs. There was no history of
recurrent sprue, sore throat and dysphagia. There was no history of hairloss. There was no
history of reduce in body weigh drastically. There was no history of having diarrhea more
than 30 days. There was no history of fever, weakness in extremities, difficulty speaking, stiff
neck, red or painful eyes, glare at light, and hearing loss. History of genital ulcers, red spots
on both palms and feet, purulent urine, injecting any illegal drug, tattoos, and got blood
transfusions on patient’s wife was denied. Patient’s wife was diagnosed genital condyloma
acuminata and gonorrhea cervicitis since two weeks ago. The patient's wife has never had sex
other than patient. The patient's wife was also tested for syphilis serology (VDRL and TPHA)
and anti-HIV with non-reactive results. The patient has been married since 10 years ago and
had three children.
On physical examination, there were no hair loss, alopecia, pharyngeal hyperemia. In
mouth, there were no vegetation, oral trush, pseudomembran, and leukoplakia. In extremities,
there was no reddish patch on palms and soles. In nails, there were no onikia sifilitika. On
venereological state, there were no erythema, edema, vesicles, ulcers, and vegetation in the
pubis, penis, scrotum, perineal and perianal. On the serological examination for syphilis, the
results were VDRL 1:32 and TPHA 1:640. The patient was also tested for anti-HIV and the
results were non-reactive. Based on anamnesis, physical examination and serological test
results, the patient was diagnosed with late latent syphilis.
The patient was given 2.4 million units of benzathine penicillin injection
intramuscular for therapy (first injection on September 9 th 2020, the patient came for
treatment 1.5 months after the VDRL and TPHA results came out), 3 times a month, then
VDRL and TPHA were checked again a month after receiving the last benzathine penicillin
injection. The results of the syphilis serology test 1 month later were VDRL 1:64 and TPHA
1: 5120. During this a month the patient did not have sex other than his wife. The patient was
receiving benzathine penicillin injection therapy of 2.4 million units intramuscular, 3 times a
month (second cycle). A month later, a serological test was performed, the results of VDRL
1:32 and TPHA 1:5120. The patient was planned to receive benzathine penicillin injection
therapy of 2.4 million units intramuscularly (third cycle), but the patient refused because it
was painful in site of inject. The patient was then given doxycycline therapy 2 x 100 mg for 1
month.

Serology Test July 22nd 2020 October 20th 2020 January 14th 2021
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 VDRL 1:32 1:64 1:32
TPHA 1:640 1:5120 1:5120

Case 2
We reported a 34 years old man that lived in Padang, came to outpatient clinic of
Dermatology and Venereology Dr. M. Djamil Hospital on December 30 th 2019 with chief
complaint patients know the results of syphilis serology was reactive when the patient
donates blood since 1 month ago. Patient did not remember the results of the syphilis
serologis. Initially, in 2017, patient underwent a medical check-up and was diagnosed with
syphilis, but patient did not remember his VDRL and TPHA results. The patient has no
complaints, so the patient does not go to the doctor for treatment. In 2019, patient donated
blood at the PMI and was tested for serological tests for syphilis. The results of test showed
Chemiluminescent Microparticle Immunoassay 2.5 (reactive), the patient was advised to seek
treatment by PMI. Patient had a history of having sex with his girlfriend 15 years ago. The
patient had one girlfriend and had sex sometimes using a condom and sometimes not using a
condom. Patient had sexual contact with his girlfriend in genito-genital. Patient never had sex
with men. The history of sexual partners experiencing genital ulcer, reddish patches on both
of palms and soles, white or gray patches on the armpits and groin, painful urination,
yellowish- whitish discharge, genital warts is denied. Since marriage, the patient has never
had sex other than his wife. Patient had sexual contact with his wife in genito-genital and not
used condom. The patient's wife was not yet screened for sexually transmitted infections.
Patient denied of having reddish patches on both of palms and soles. He also denied having
ulcer that didn’t painful and vesicles on his genital. There was no history of got transfusion,
tatoo and injecting any ilegal drugs. There was no history of recurrent sprue, sore throat and
dysphagia. There was no history of hairloss. There was no history of reduce in body weigh
drastically. There was no history of having diarrhea more than 30 days. There was no history
of fever, weakness in extremities, difficulty speaking, stiff neck, red or painful eyes, glare at
light, and hearing loss. History of genital ulcers, red spots on both palms and feet, purulent
urine, injecting any illegal drug, tattoos, and got blood transfusions on patient’s wife was
denied.
On physical examination, there were no hair loss, alopecia, pharyngeal hyperemia. In
mouth, there were no vegetation, oral trush, pseudomembran, and leukoplakia. In extremities,

5
there was no reddish patch on palms and soles. In nails, there were no onikia sifilitika. On
venereological state, there were no erythema, edema, vesicles, ulcers, and vegetation in the
pubis, penis, scrotum, perineal and perianal. On the serological examination for syphilis, the
results were VDRL 1:4 and TPHA 1:80. The patient was also tested for anti-HIV and the
results were non-reactive. Based on anamnesis, physical examination and serological test
results, the patient was diagnosed with late latent syphilis.
The patient was given 2.4 million units of benzathine penicillin injection
intramuscular for therapy (first injection on December 30 th 2019), three times a month. The
results of the syphilis serology test a month later were VDRL 1:2 and TPHA 1: 80. Three
months later, a serological test was performed, the results of VDRL 1:4 and TPHA 1:160.
During this 3 month, the patient did not have sex other than his wife. The patient was given
benzathine penicillin injection therapy 2.4 million units intramuscular, three times a month
(second cycle). After a month later, the results of VDRL 1:2 and TPHA 1:80. VDRL and
TPHA examinations were carried out 3 months later.

Serology December 30th February 17th June 17th 2020 September 25th
Test 2019 2020 2021
VDRL 1:4 1:2 1:4 1:2
TPHA 1:80 1:80 1:160 1:80

Case 3
We reported a 53 years old man that lived in Padang, came to outpatient clinic
department of dermatology and venereology Dr. M. Djamil Hospital on June 4 th 2018 with
chief complaint patients know the results of syphilis serology was reactive when the patient
donates blood. The results of laboratory tests at PMI are Chemiluminescent Microparticle
Immunoassay 7.45 (reactive). Patient had married and no history of having sex with other
woman and men. Patient never had sex with men. The history of sexual partners experiencing
genital ulcer, reddish patches on both of palms and soles, white or gray patches on the
armpits and groin, painful urination, yellowish-whitish discharge, genital warts is denied.
Patient denied of having reddish patches on both of palms and soles. The patient's wife was
not yet screened for sexually transmitted infections. He also denied having ulcer that didn’t
painful and vesicles on his genital. There was no history of got transfusion, tatoo and
injecting any ilegal drugs. There was no history of recurrent sprue, sore throat and dysphagia.

6
There was no history of hairloss. There was no history of reduce in body weigh drastically.
There was no history of having diarrhea more than 30 days. There was no history of fever,
weakness in extremities, difficulty speaking, stiff neck, red or painful eyes, glare at light, and
hearing loss.
On physical examination, there were no hair loss, alopecia, pharyngeal hyperemia. In
mouth, there were no vegetation, oral trush, pseudomembran, and leukoplakia. In extremities,
there was no reddish patch on palms and soles. In nails, there were no onikia sifilitika. On
venereological state, there were no erythema, edema, vesicles, ulcers, and vegetation in the
pubis, penis, scrotum, perineal and perianal. On the serological examination for syphilis, the
results were VDRL 1:8 and TPHA 1:640. The patient was also tested for anti-HIV and the
results were non-reactive. Based on anamnesis, physical examination and serological test
results, the patient was diagnosed with late latent syphilis.
The patient was given 2.4 million units of benzathine penicillin injection
intramuscular for therapy (first injection on June 4th 2018), three times a month. The results
of the syphilis serology test a month later were VDRL 1:8 and TPHA 1:640 (second cycle).
During this a month, the patient did not have sex other than his wife. Two months later, a
serological test was performed, the results of VDRL 1:4 and TPHA 1:640. Four months later,
a serological test was performed, the results of VDRL 1:8 and TPHA 1:640. The patient was
given benzathine penicillin injection therapy 2.4 million units intramuscular, three times a
month (third cycle). After 1 month later, the results of VDRL 1:1 and TPHA 1:160. Three
months later, a serological test was performed, the results of VDRL 1:8 and TPHA 1:160.
The patient was advised to do the VDRL and TPHA tests in 6 months later, but the patient
could not do the syphilis serology test. The patient did the examination after 11 months later
and VDRL was 1:4, then TPHA 1:40. VDRL and TPHA examinations were carried out 6
months later.

Serology June 4th July 26th October March May 8th August July 10th
Test 2018 2018 31th 2018 15th 2019 2019 30th 2019 2020
VDRL 1:8 1:2 1:4 1:8 1:1 1:8 1:4
TPHA 1:640 1:80 1:160 1:640 1:160 1:160 1/40

DISCUSSION

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 Latent syphilis is defined as syphilis characterized by seroreactivity without other
evidence of primary, secondary, or tertiary disease. Persons can receive a diagnosis of early
latent syphilis if during the year preceding the diagnosis, they had 1) a documented
seroconversion or a sustained (>2 week) fourfold or greater increase in nontreponemal test
titers; 2) unequivocal symptoms of primary or secondary syphilis; or 3) a sex partner
documented to have primary, secondary, or early latent syphilis. In addition, for persons with
reactive nontreponemal and treponemal tests whose only possible exposure occurred during
the previous 12 months, early latent syphilis can be assumed. In the absence of these
conditions, an asymptomatic person should be considered to have latent syphilis.
Nontreponemal serologic titers usually are higher early in the course of syphilis infection.
However, early latent syphilis cannot be reliably diagnosed solely on the basis of
nontreponemal titers. All persons with latent syphilis should have careful examination of all
accessible mucosal surfaces (the oral cavity, perianal area, perineum and vagina in women,
and underneath the foreskin in uncircumcised men) to evaluate for mucosal lesions.1
Based on data from case series and clinical trials and long clinical experience,
penicillin is the recommended treatment for all stages of syphilis, with the preparation, dose,
and length of treatment dependent on the clinical manifestations, stage of disease, and age of
the patient. Benzathine penicillin G, the recommended preparation of penicillin for most
stages of syphilis, has a long half-life, which is critical therapeutically because of the slow
dividing time of T. pallidum. Treatment Guidelines from the CDC is that a single injection of
benzathine penicillin, 2.4 million units, be given in early latent syphilis (less than 1 year), but
that three injections be given at weekly intervals for late latent syphilis or syphilis of
unknown duration.1 Three cases that we reported were diagnosed late latent syphilis and were
treated with Benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4
million units intramuscularly each at one-week intervals.
Duration of treponemicidal level of antimicrobials should be at least 7–10 days to
cover a number of division times (30– 33 h). Longer duration of treatment is needed as the
duration of infection increases (more relapses have been seen in later stages after short
courses of treatment), possibly because of more slowly dividing treponemes in late syphilis.
Long acting Benzathine penicillin G 2.4 million units is the treatment of first choice, which
provides a treponemicidal penicillin level in blood for up to 21–28 days. Benzathine
penicillin G is also widely used because of efficacy and ease of treatment.5
Quantitative VDRL or RPR tests may both be used for monitoring the disease
progression and effectiveness of treatment at follow-up visits. Titre must be obtained on the
8
very first day of treatment, that is to provide a baseline for measuring a decrease in antibody
titres. Serum should be obtained at 1, 3 and every 6 months subsequently, the identical Non-
treponemal test (NTT) should be used and all samples tested in the same laboratory. This
should be continued until the NTT becomes negative, attains a low plateau (1:1 – 1:4,
sustained for 1 year). Patients with higher titres should remain under follow-up.5
A fourfold titer increase following appropriate treatment indicates reinfection or
treatment failure—the latter in some cases associated with neurosyphilis—with treatment
depending on which of those is believed to have caused the increase. Reinfection must be
assessed by clinical history and physical examination. If treatment failure cannot be ruled out,
the patient should be treated with 7.2 million units of benzathine penicillin G (divided into 3
weekly doses); CSF examination should be performed to determine whether neurosyphilis is
present, and the patient also should be treated for neurosyphilis. A cerebro spinal fluid
examination should be performed if 1) a sustained (>2 weeks) fourfold increase or greater in
titer is observed, 2) an initially high titer (≥1:32) fails to decline at least fourfold within 12–
24 months of therapy, or 3) signs or symptoms attributable to syphilis develop. 1 In case 3, the
patient should have a CSF examination to rule out asymptomatic neurosyphilis, because
VDRL titers fails to decline fourfold in 24 months of therapy.
Few studies have been done on the serologic response to treatment in late latent
disease. A study by Fiumara suggests that the decline in titer may be more gradual and that
low titers persist in approximately 50% of patients after 2 years of observation. The majority
of patients had nonreactive nontreponemal tests 5 years after treatment. 6 In the first case, the
patient has received injection therapy of benzatine penicillin 7.2 million units for 3 cycles,
but there has not been a fourfold decrease in VDRL titer. Venereal Disease Research
Laboratory titer up and down from the initial titer, so that this patient has not responded to
benzathine penicillin and a follow-up is required. In the second case, the patient was treated
with benzathine penicillin injection for 2 cycles. The decrease in VDRL titer after 8 months
was 2 times that of baseline titer and the patient responded to benzathine penicillin therapy.
In the third patient, the patient was treated with benzathine penicillin for 3 cycles, the patient
was not regularly controlled. The VDRL titer up and down, beside that the VDRL titer
decreased 2 times from initial titer after 2 years of follow-up. Patients still respond to
benzathine penicillin treatment.

CONCLUSION

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 Benzathine penicillin is the therapy of choice in the treatment of advanced latent
syphilis. The patient is declared a response to therapy if there is a decrease in the
VDRL titer and the patient is declared cured if there is a decrease in the VDRL titer 4
times

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anna l, Erik AH, David J margolis, Michael AJM, et al., editors. Fitzpatricks
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European guidelines on the management syphilis 2014. Journal of European Academy
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