The FDA has listed penicillin G benzathine injectable suspension products (Bicillin L-A®) on their drug shortage webpage, noting limited supply due to increased demand. The FDA website includes an expected duration for the shortage. CDC continues to monitor the situation and will post updates as needed.
On 1/16/2024, the FDA announced that they have exercised enforcement discretion for a temporary importation and use of Extencillin (benzathine benzylpenicillin injection, powder, for suspension) to mitigate the effects of the Bicillin L-A® drug shortage. See more in this CDC letter.
Bicillin L-A® is the first-line recommended treatment for syphilis and the only recommended treatment option for some patients.
During this time, programs can see Clinical Reminders during Bicillin L-A® Shortage for priority actions they can take.
Syphilis is a systemic disease caused by T. pallidum. The disease has been divided into stages on the basis of clinical findings, which guide treatment and follow-up. Persons who have syphilis might seek treatment for signs or symptoms. Primary syphilis classically presents as a single painless ulcer or chancre at the site of infection but can also present with multiple, atypical, or painful lesions (564). Secondary syphilis manifestations can include skin rash, mucocutaneous lesions, and lymphadenopathy. Tertiary syphilis can present with cardiac involvement, gummatous lesions, tabes dorsalis, and general paresis.
Latent infections (i.e., 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 classified as late latent syphilis or latent syphilis of unknown duration.
T. pallidum can infect the CNS, which can occur at any stage of syphilis and result in neurosyphilis. Early neurologic clinical manifestations or syphilitic meningitis (e.g., cranial nerve dysfunction, meningitis, meningovascular syphilis, stroke, and acute altered mental status) are usually present within the first few months or years of infection. Late neurologic manifestations (e.g., tabes dorsalis and general paresis) occur 10 to >30 years after infection.
Infection of the visual system (ocular syphilis) or auditory system (otosyphilis) can occur at any stage of syphilis but is commonly identified during the early stages and can present with or without additional CNS involvement. Ocular syphilis often presents as panuveitis but can involve structures in both the anterior and posterior segment of the eye, including conjunctivitis, anterior uveitis, posterior interstitial keratitis, optic neuropathy, and retinal vasculitis. Ocular syphilis can result in permanent vision loss. Otosyphilis typically presents with cochleo-vestibular symptoms, including tinnitus, vertigo, and sensorineural hearing loss. Hearing loss can be unilateral or bilateral, have a sudden onset, and progress rapidly. Otosyphilis can result in permanent hearing loss.
Darkfield examinations and molecular tests for detecting T. pallidum directly from lesion exudate or tissue are the definitive methods for diagnosing early syphilis and congenital syphilis (565). Although no T. pallidum direct-detection molecular NAATs are commercially available, certain laboratories provide locally developed and validated PCR tests for detecting T. pallidum DNA. A presumptive diagnosis of syphilis requires use of two laboratory serologic tests: a nontreponemal test (i.e., Venereal Disease Research Laboratory [VDRL] or rapid plasma reagin [RPR] test) and a treponemal test (i.e., the T. pallidum passive particle agglutination [TP-PA] assay, various EIAs, chemiluminescence immunoassays [CIAs] and immunoblots, or rapid treponemal assays) (566–568). At least 18 treponemal-specific tests are cleared for use in the United States. Use of only one type of serologic test (nontreponemal or treponemal) is insufficient for diagnosis and can result in false-negative results among persons tested during primary syphilis and false-positive results among persons without syphilis or previously treated syphilis.
False-positive nontreponemal test results can be associated with multiple medical conditions and factors unrelated to syphilis, including other infections (e.g., HIV), autoimmune conditions, vaccinations, injecting drug use, pregnancy, and older age (566,569). Therefore, persons with a reactive nontreponemal test should always receive a treponemal test to confirm the syphilis diagnosis (i.e., traditional algorithm). Nontreponemal test antibody titers might correlate with disease activity and are used for monitoring treatment response. Serum should be diluted to identify the highest titer, and results should be reported quantitatively. A fourfold change in titer, equivalent to a change of two dilutions (e.g., from 1:16 to 1:4 or from 1:8 to 1:32), is considered necessary for demonstrating a clinically significant difference between two nontreponemal test results obtained by using the same serologic test, preferably from the same manufacturer to avoid variation in results. Sequential serologic tests for a patient should be performed using the same testing method (VDRL or RPR), preferably by the same laboratory. VDRL and RPR are equally valid assays; however, quantitative results from the two tests cannot be compared directly with each other because the methods are different, and RPR titers frequently are slightly higher than VDRL titers.
Nontreponemal test titers usually decrease after treatment and might become nonreactive with time. However, for certain persons, nontreponemal antibodies might decrease less than fourfold after treatment (i.e., inadequate serologic response) or might decline appropriately but fail to serorevert and persist for a long period. Atypical nontreponemal serologic test results (e.g., unusually high, unusually low, or fluctuating titers) might occur regardless of HIV status. When serologic tests do not correspond with clinical findings indicative of primary, secondary, or latent syphilis, presumptive treatment is recommended for persons with risk factors for syphilis, and use of other tests (e.g., biopsy for histology and immunostaining and PCR of lesion) should be considered. For the majority of persons with HIV infection, serologic tests are accurate and reliable for diagnosing syphilis and evaluating response to treatment.
Treponemal Tests and Reverse Sequence Algorithm
The majority of patients who have reactive treponemal tests will have reactive tests for the remainder of their lives, regardless of adequate treatment or disease activity. However, 15%–25% of patients treated during the primary stage revert to being serologically nonreactive after 2–3 years (570). Treponemal antibody titers do not predict treatment response and therefore should not be used for this purpose.
Clinical laboratories sometimes screen syphilis serologic samples by using automated treponemal immunoassays, typically by EIA or CIA (571–573). This reverse sequence algorithm for syphilis testing can identify persons previously treated for syphilis, those with untreated or incompletely treated syphilis, and those with false-positive results that can occur with a low likelihood of infection (574). Persons with a positive treponemal screening test should have a standard quantitative nontreponemal test with titer performed reflexively by the laboratory to guide patient management decisions. If the nontreponemal test is negative, the laboratory should perform a treponemal test different from the one used for initial testing, preferably TP-PA or treponemal assay based on different antigens than the original test, to adjudicate the results of the initial test.
If a second treponemal test is positive (e.g., EIA reactive, RPR nonreactive, TP-PA reactive), persons with a history of previous treatment will require no further management unless sexual history indicates a reexposure. In this instance, a repeat nontreponemal test 2–4 weeks after a confirmed medical history and physical examination is recommended to evaluate for early infection. Those without a history of treatment for syphilis should be offered treatment. Unless a medical history or results of a physical examination indicate a recent infection, previously untreated persons should be treated for syphilis of unknown duration or late latent syphilis.
If the second treponemal test is negative (e.g., EIA reactive, RPR nonreactive, TP-PA nonreactive) and the epidemiologic risk and clinical probability for syphilis are low, further evaluation or treatment is not indicated.
Multiple studies demonstrate that high quantitative index values or high signal-to-cutoff ratio from treponemal EIA or CIA tests correlate with TP-PA positivity, which might eliminate the need for additional confirmatory testing; however, the range of index values varies among different treponemal immunoassays, and the values that correspond to high levels of reactivity with confirmatory testing might differ by immunoassay (567,575–582).
Cerebrospinal Fluid Evaluation
Further testing with CSF evaluation is warranted for persons with clinical signs of neurosyphilis (e.g., cranial nerve dysfunction, meningitis, stroke, acute or chronic altered mental status, or loss of vibration sense). All patients with ocular symptoms and reactive syphilis serology need a full ocular examination, including cranial nerve evaluation. If cranial nerve dysfunction is present, a CSF evaluation is needed. Among persons with isolated ocular symptoms (i.e., no cranial nerve dysfunction or other neurologic abnormalities), confirmed ocular abnormalities on examination, and reactive syphilis serology, a CSF examination is unnecessary before treatment. CSF analysis can be helpful in evaluating persons with ocular symptoms and reactive syphilis serology who do not have ocular findings or cranial nerve dysfunction on examination. Among patients with isolated auditory abnormalities and reactive syphilis serology, CSF evaluation is likely to be normal and is unnecessary before treatment (583,584).
Laboratory testing is helpful in supporting the diagnosis of neurosyphilis; however, no single test can be used to diagnose neurosyphilis in all instances. Diagnosis of neurosyphilis depends on a combination of CSF tests (e.g., CSF cell count, protein, or reactive CSF-VDRL) in the presence of reactive serologic test (nontreponemal and treponemal) results and neurologic signs and symptoms. CSF laboratory abnormalities are common for persons with early syphilis and are of unknown medical significance in the absence of neurologic signs or symptoms (585). CSF-VDRL is highly specific but insensitive. For a person with neurologic signs or symptoms, a reactive CSF-VDRL (in the absence of blood contamination) is considered diagnostic of neurosyphilis.
When CSF-VDRL is negative despite clinical signs of neurosyphilis, reactive serologic tests results, lymphocytic pleocytosis, or protein, neurosyphilis should be considered. In that instance, additional evaluation by using fluorescent treponemal-antibody absorption (FTA-ABS) or TP-PA testing on CSF might be warranted. The CSF FTA-ABS test is less specific for neurosyphilis than the CSF-VDRL but is highly sensitive. Fewer data are available regarding CSF TP-PA; however, the sensitivity and specificity appear similar to the CSF FTA-ABS (586). Neurosyphilis is highly unlikely with a negative CSF FTA-ABS or TP-PA test, especially among persons with nonspecific neurologic signs and symptoms (587).
Among persons with HIV infection, CSF leukocyte count can be elevated (>5 WBCs/mm3); the association with CSF leukocyte count and plasma HIV viral suppression has not been well characterized. Using a higher cutoff (>20 WBCs/mm3) might improve the specificity of neurosyphilis diagnosis among this population (588).
Penicillin G, administered parenterally, is the preferred drug for treating patients in all stages of syphilis. The preparation used (i.e., 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 (>1 years’ duration) and tertiary syphilis requires 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.
Selection of the appropriate penicillin preparation is important because T. pallidum can reside in sequestered sites (e.g., the CNS and aqueous humor) that are poorly accessed by certain forms of penicillin. Combinations of benzathine penicillin, procaine penicillin, and oral penicillin preparations are not considered appropriate for syphilis treatment. Reports have indicated that practitioners have inadvertently prescribed combination long- and short-acting benzathine-procaine penicillin (Bicillin C-R) instead of the standard benzathine penicillin product (Bicillin L-A) recommended in the United States for treating primary, secondary, and latent syphilis. Practitioners, pharmacists, and purchasing agents should be aware of the similar names of these two products to avoid using the incorrect combination therapy agent for treating syphilis (589).
Penicillin’s effectiveness for treating syphilis was well established through clinical experience even before the value of randomized controlled clinical trials was recognized. Therefore, approximately all recommendations for treating syphilis are based not only on clinical trials and observational studies, but on many decades of clinical experience.
Parenteral penicillin G is the only therapy with documented efficacy for syphilis during pregnancy. Pregnant women with syphilis at any stage who report penicillin allergy should be desensitized and treated with penicillin (see Management of Persons Who Have a History of Penicillin Allergy).
The Jarisch-Herxheimer reaction is an acute febrile reaction frequently accompanied by headache, myalgia, and fever that can occur within the first 24 hours after the initiation of any syphilis therapy; it is a reaction to treatment and not an allergic reaction to penicillin. Patients should be informed about this possible adverse reaction and how to manage it if it occurs. The Jarisch-Herxheimer reaction occurs most frequently among persons who have early syphilis, presumably because bacterial loads are higher during these stages. Antipyretics can be used to manage symptoms; however, they have not been proven to prevent this reaction. The Jarisch-Herxheimer reaction might induce early labor or cause fetal distress in pregnant women; however, this should not prevent or delay therapy (590) (see Syphilis During Pregnancy).
Management of Sex Partners
Sexual transmission of T. pallidum is thought to occur only when mucocutaneous syphilitic lesions are present. Such manifestations are uncommon after the first year of infection. Persons exposed through sexual contact with a person who has primary, secondary, or early latent syphilis should be evaluated clinically and serologically and treated according to the following recommendations:
- Persons who have had sexual contact with a person who receives a diagnosis of primary, secondary, or early latent syphilis <90 days before the diagnosis should be treated presumptively for early syphilis, even if serologic test results are negative.
- Persons who have had sexual contact with a person who receives a diagnosis of primary, secondary, or early latent syphilis >90 days before the diagnosis should be treated presumptively for early syphilis if serologic test results are not immediately available and the opportunity for follow-up is uncertain. If serologic tests are negative, no treatment is needed. If serologic tests are positive, treatment should be based on clinical and serologic evaluation and syphilis stage.
- In certain areas or among populations with high syphilis infection rates, health departments recommend notification and presumptive treatment of sex partners of persons with syphilis of unknown duration who have high nontreponemal serologic test titers (i.e., >1:32) because high titers might be indicative of early syphilis. These partners should be managed as if the index patient had early syphilis.
- Long-term sex partners of persons who have late latent syphilis should be evaluated clinically and serologically for syphilis and treated on the basis of the evaluation’s findings.
- The following sex partners of persons with syphilis are considered at risk for infection and should be confidentially notified of the exposure and need for evaluation: partners who have had sexual contact within 3 months plus the duration of symptoms for persons who receive a diagnosis of primary syphilis, within 6 months plus duration of symptoms for those with secondary syphilis, and within 1 year for persons with early latent syphilis.