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Benzathine Penicillin

Editor: Kaitlyn Reti Updated: 2/12/2024 1:48:18 AM


Benzathine penicillin is formulated from 2 penicillin G molecules reacting with diphenylethylene diamine. The drug is active against Gram-positive bacteria, including beta-hemolytic streptococci (groups A, B, C, G, H, L, and M), Treponema pallidum, and T. carateum. There has been no reported resistance to benzathine penicillin in Streptococcus pyogenes.[1][2][3][4][5]

FDA-Approved Indications

  1. Acute glomerulonephritis
  2. Respiratory tract infections
  3. Rheumatic fever and chorea
  4. Rheumatic heart disease
  5. Syphilis and another venereal disease

Specific indications for adult and pediatric populations are as follows:


1. Upper respiratory infection, group A streptococci

  • Secondary prevention of glomerulonephritis
  • Secondary prevention of rheumatic fever

2. Pharyngitis, group A streptococci (Infectious Diseases Society of America [IDSA] guidelines)

  • Acute and chronic carrier treatment

3. Syphilis (CDC)

  • Primary, secondary, and early latent (less than 1-year duration)
  • Late latent, latent with unknown duration, or tertiary syphilis (with normal cerebrospinal fluid examination)
  • Neurosyphilis, including ocular syphilis (not indicated for use) [6]

4. Yaws, bejel, and pinta (dermal infections caused by Treponema pallidum and T. carateum)


1. Upper respiratory infection, group A streptococci (eg, pharyngitis)

2. Primary prevention of rheumatic fever

3. Secondary prevention of rheumatic fever [7]

4. Pharyngitis/tonsillitis, group A streptococci (IDSA)

  • Acute and chronic carrier state

Off-Label Uses

Syphilis (CDC)

  • Primary, secondary, and early latent (less than 1-year duration)
  • Late latent

Mechanism of Action

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Mechanism of Action

Benzathine penicillin (benzylpenicillin or penicillin G) is a beta-lactam antimicrobial used to treat infections caused by gram-positive cocci, particularly streptococcal infections. Beta-lactams are bactericidal antimicrobials. These antimicrobials inhibit the biosynthesis of the cell wall peptidoglycan during the stage of active multiplication by inhibiting bacterial peptidoglycan transpeptidase. This results in an osmotically unstable cell wall, leading to cell wall lysis and subsequent destruction of the bacterial cell, leading to bacterial cellular death.

Mechanism of Resistance

Benzathine penicillin does not have antimicrobial activity against penicillinase-producing bacteria or organisms resistant to beta-lactams because of penicillin-binding protein alterations.



Benzathine penicillin is rapidly absorbed following intramuscular or subcutaneous injection, leading to high initial blood levels, although these are transient. Oral absorption is poor as the drug is susceptible to acid-catalyzed hydrolysis.


Benzathine penicillin exhibits a volume of distribution of 0.53 to 0.567. It is 45% to 68% protein-bound, primarily to albumin.


Benzathine penicillin is metabolized to 6-aminopenicillanic acid and penicilloic acid. Small amounts of the drug seem to undergo hydroxylation to active metabolites excreted in the urine.


Benzathine penicillin is renally eliminated. Non-renal clearance occurs via hepatic metabolism (including CYP450 enzymes) and biliary excretion to a lesser extent.


Dosage Forms

Benzathine penicillin is available as an injectable suspension that is administered intramuscularly. The medication should be warmed to room temperature before administration to lessen the pain associated with the injection, and it should not be given near an artery or nerve. In adults, the injection is administered to the upper outer quadrant of the buttocks. In children younger than 2, the injection should be administered to the mid-lateral muscle of the thigh. The injection site should be rotated on repeat doses.

Benzathine penicillin is opaque and viscous with very low solubility. Therefore, the antimicrobial is slowly released from the injection site and hydrolyzed to penicillin G. Due to the slow absorption and the hydrolysis, the drug concentration in the blood remains lower for a prolonged period. After a 1.2 million unit injection, adults have detectable drug concentrations for 14 days or longer.

The antimicrobial typically is manufactured in 600,000 units/mL, 1.2 million units/2 mL, or 2.4 million units/4 mL syringes. The antimicrobial should be stored in a refrigerator from 36 °F to 46 °F (2 °C to 8 °C) and never frozen. Dosing recommendations are as follows:

Adult Dosing

  • Pharyngitis/tonsillitis, group A streptococci (1.2 million units, intramuscularly [IM] x 1)
  • Upper respiratory infection, group A streptococci that are mild to moderate and are susceptible to low, prolonged concentrations of benzathine penicillin (1.2 million units, IM x 1)
  • Secondary prevention of glomerulonephritis, prophylaxis for patients with a history of acute glomerulonephritis (1.2 million units IM every 4 weeks or 600,000 units IM twice monthly)
  • Secondary prevention (prophylaxis) of rheumatic fever (1.2 million units IM every 3 to 4 weeks or 600,000 units IM twice monthly)
  • Syphilis: Primary, secondary, or latent less than 1 year (2.4 million units IM x 1, may repeat dose x 1 after 1 week in pregnant patients); latent greater than 1 year (2.4 million units IM weekly for 3 weeks) [8]
  • Yaws, bejel, and pinta (1.2 million units IM x 1)

Special Patient Populations

Hepatic impairment

Dose adjustments for patients with hepatic impairment are undefined.

Renal impairment

Dose adjustments in patients with renal impairment are as follows:

  • Creatinine clearance 10 to 50 mL/min: decrease dose by 25%
  • Creatinine clearance less than 10 mL/min: decrease dose by 50% to 80%
  • Hemodialysis: give dose after dialysis
  • Peritoneal dialysis: decreased dose by 50% to 80%

Pregnant women

Benzathine penicillin is pregnancy category B. Reproduction studies performed in mice, rats, and rabbits have revealed no evidence of harm to the fetus. Human experience with penicillin during pregnancy has not been shown to have any adverse effects on the fetus. However, studies with pregnant women are inadequate or not well-controlled and cannot conclusively report the harmful effects of penicillin medications on the fetus.

Breastfeeding women

Soluble penicillin G is excreted in breast milk. Clinicians should exercise caution in this patient population.[9]

Pediatric patients

Pediatric Dosing

  • Pharyngitis/tonsillitis, group A streptococci:
    • Acute treatment:
      • <27 kg = 600,000 units IM x 1
      • >27 kg = 1.2 million units IM x 1
    • Chronic carrier treatment:
      • <27 kg = 600,000 units IM x 1, in combination with oral rifampin
      • >27 kg = 1.2 million units IM x 1, in combination with oral rifampin
  • Upper respiratory infection, group A streptococci:
    • <27 kg = 300,000 – 600,000 units IM x 1
    • >27 kg = 900,000 units IM x 1
  • Secondary prevention of rheumatic fever
    • <27 kg = 600,000 units IM every 3 to 4 weeks
    • >27 kg = 1.2 million units IM every 3 to 4 weeks
  • Syphilis
    • Acquired
      • Primary or secondary, or latent, <1-year duration: 50,000 units/kg/dose IM X 1; maximum 2.4 million units/dose.
      • Latent of >1-year duration: 50,000 units/kg/dose IM weekly for 3 weeks; maximum 2.4 million units/dose.
    • Congenital: 
      • Neonates: 50,000 units/kg/dose IM X 1; maximum 2.4 million units/dose.
      • Infants/children: 50,000 units/kg/dose IM weekly for 3 weeks; maximum 2.4 million units/dose.

Older patients

Clinical studies have not included sufficient numbers of patients older than 65 to determine whether they respond differently than younger patients. Reported clinical experience has not identified any differences delineating older and younger patients. Generally, dosing in older patients should be at the lower end of any dose range due to the increased potential for hepatic or renal impairment.

Adverse Effects

Patients generally tolerate benzathine penicillin well, with pain from the injection being the most common concern. Hypersensitivity reactions are another possible adverse event. Patients with a previous history of hypersensitivity to penicillin or those with a history of asthma, hay fever, allergies, or urticaria are at higher risk of hypersensitivity reactions. Hypersensitivity reactions can be severe or fatal and include the type I IgE-mediated reaction, also known as anaphylaxis. This type I hypersensitivity reaction typically includes urticarial skin rash, itching, wheezing, dyspnea, nausea, vomiting, and diarrhea and can progress to hemodynamic instability and death. Any previous anaphylactic reaction or severe skin reaction (eg, Steven-Johnson or toxic epidermal necrosis) to any penicillin is a contraindication for use. There have been previous reports that patients with anaphylactic or severe skin reactions from cephalosporins or carbapenems will have a type of cross-reactivity reaction that will also have serious adverse events when administered any penicillin medication. These reports are believed to be much lower than previously suspected. 

Other rare, potentially serious adverse events include C. difficile-associated diarrhea, hemolytic anemia, leukopenia, thrombocytopenia, nephrotoxicity, and neuropathy. Other less severe adverse reactions include mild rash/urticaria, diarrhea, nausea, vomiting, and elevated BUN or creatinine.

Superinfections can result from prolonged use. A superinfection can occur up to 2 months of post-antimicrobial treatment. These potentially fatal infections include C. difficile-associated diarrhea and pseudomembranous colitis.[10][11][12]

Drug-Drug Interactions

As a bacteriostatic antibiotic, tetracycline may antagonize the bacteriocidal effect of penicillin; concurrent use should be avoided. Concurrent use of probenecid with penicillin can increase penicillin levels by slowing the drug's excretion rate via competitive inhibition of the renal tubular mechanism.


Benzathine penicillin is contraindicated in patients with previous anaphylactic or severe skin reactions to penicillin (eg, Steven-Johnson or toxic epidermal necrosis). There have been reports of patients with anaphylactic or severe skin reactions from cephalosporins or carbapenems having a type of cross-reactivity reaction that also results in serious adverse events when they are administered any penicillin antimicrobial, including benzathine penicillin, but these reports are believed to be much less prevalent than previously suspected.

Box Warning

Benzathine penicillin should never be injected intravenously or admixed with other intravenous medications. Reports exist of inadvertent IV administration of benzathine penicillin associated with cardiorespiratory arrest and death.[13]


Clinicians should use this drug with caution in patients with a seizure disorder, especially in patients with renal impairment, due to a potential increase in the risk of seizures.


Creatinine levels at baseline are recommended. Observe for signs and symptoms of hypersensitivity reactions, including anaphylaxis. Prescribers and other healthcare team members must also monitor for a lack of therapeutic response, which could be a sign of superinfection.[14]


Since a healthcare practitioner administers the medication by injection, overdoses are rare. An overdose has the potential to cause neuromuscular irritability or convulsive seizures.

Enhancing Healthcare Team Outcomes

Benzathine penicillin is often administered by various interprofessional healthcare team members, including physicians, internists, infectious disease experts, nurse practitioners, or physician assistants. While the drug is relatively safe, observing the patient for an allergic reaction is crucial. Empirical use of this drug can lead to superinfections. Nursing staff should counsel the patient on how to take the medication and answer any questions they may have regarding their antimicrobial therapy. The pharmacist can reiterate administration points and advise the patient to take the entire course of medication and not stop taking the drug if they begin to feel better. Additionally, patients should inform the nurse or prescribing clinician of any adverse events or signs of therapeutic failure or significant adverse effects. In this way, all interprofessional team members can play a role in successful therapeutic patient outcomes with minimal adverse events.



Walker GJ, Walker D, Molano Franco D, Grillo-Ardila CF. Antibiotic treatment for newborns with congenital syphilis. The Cochrane database of systematic reviews. 2019 Feb 15:2(2):CD012071. doi: 10.1002/14651858.CD012071.pub2. Epub 2019 Feb 15     [PubMed PMID: 30776081]

Level 1 (high-level) evidence


Ndeikoundam Ngangro N, Viriot D, Fournet N, Pioche C, De Barbeyrac B, Goubard A, Dupin N, Berçot B, Fouéré S, Alcaraz I, Ohayon M, Spenatto N, Vernay-Vaisse C, referents for the regional offices of the French national public health agency, Pillonel J, Lot F. Bacterial sexually transmitted infections in France: recent trends and patients' characteristics in 2016. Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin. 2019 Jan:24(5):. doi: 10.2807/1560-7917.ES.2019.24.5.1800038. Epub     [PubMed PMID: 30722812]


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Struyve M, Meersseman W, Van Moerkercke W. Primary syphilitic proctitis : case report and literature review. Acta gastro-enterologica Belgica. 2018 Jul-Sep:81(3):430-432     [PubMed PMID: 30350534]

Level 3 (low-level) evidence


Khan A, Sutcliffe N, Jawad AS. An old disease re-emerging: acute rheumatic fever. Clinical medicine (London, England). 2018 Oct:18(5):400-402. doi: 10.7861/clinmedicine.18-5-400. Epub     [PubMed PMID: 30287435]


Gozdas HT, Dogan A. Is Benzathine Penicillin the Treatment of Choice in Neurosyphilis? The American journal of medicine. 2023 Oct:136(10):e208. doi: 10.1016/j.amjmed.2023.05.022. Epub     [PubMed PMID: 37734810]


Dündaröz R, Ulucan H, Denli M, Karapinar K, Aydin HI, Baltaci V. Evaluation of DNA damage using the comet assay in children on long-term benzathine penicillin for secondary prophylaxis of rheumatic fever. Pediatrics international : official journal of the Japan Pediatric Society. 2001 Jun:43(3):276-80     [PubMed PMID: 11380924]


Kingston M, Carlin E. Treatment of sexually transmitted infections with single-dose therapy: a double-edged sword. Drugs. 2002:62(6):871-8     [PubMed PMID: 11929335]


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. Benzathine Penicillin G. Drugs and Lactation Database (LactMed®). 2006:():     [PubMed PMID: 30000197]


Holland JV, Hardie K, de Dassel J, Ralph AP. Rheumatic Heart Disease Prophylaxis in Older Patients: A Register-Based Audit of Adherence to Guidelines. Open forum infectious diseases. 2018 Jun 1:5(6):ofy125. doi: 10.1093/ofid/ofy125. Epub 2018 May 29     [PubMed PMID: 29942824]


Montagnat OD, Webster GR, Bulitta JB, Landersdorfer C, Wyber R, Sheel M, Carapetis JR, Boyd BJ. Lessons learned in the development of sustained release penicillin drug delivery systems for the prophylactic treatment of rheumatic heart disease (RHD). Drug delivery and translational research. 2018 Jun:8(3):729-739. doi: 10.1007/s13346-018-0482-z. Epub     [PubMed PMID: 29404981]


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