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

Benzathine penicillin is FDA-approved to treat the following: 

Adult

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)

4. Yaws, bejel, and pinta

Pediatric

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

2. Primary prevention of rheumatic fever

3. Secondary prevention of rheumatic fever

4. Pharyngitis, group A streptococci (IDSA)

• Acute and chronic carrier state

5. Syphilis (off-label population) (CDC)

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

 FDA Labeled Indications

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

Benzathine penicillin is in a class of beta-lactam antimicrobials. Beta-lactams are bactericidal antimicrobials. This type of antimicrobial inhibits the biosynthesis of the cell wall peptidoglycan during the stage of active multiplication. It inhibits bacterial peptidoglycan transpeptidase. This results in an osmotically unstable cell wall, leading to lysis of the cell wall, subsequent destruction of the bacterial cell, and death.

Benzathine penicillin is available as an injectable suspension that is administered intramuscularly, not intravenous, intra-arterial, or subcutaneous. 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, administer the injection to the upper outer quadrant of the buttocks. In children less than 2 years old, administer the injection to the mid-lateral muscle of the thigh, not the gluteal region, and rotate the injection site on repeat doses.

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

The antimicrobial typically is manufactured in 600,000 units/1 mL, 1.2 million units/2 mL, or 2.4 million units/4 mL syringes. The antimicrobial is to be stored in a refrigerator from 36 to 46 degrees F (2 to 8 degrees C), never frozen. Dosing recommendations are as follows:

Adult

• Pharyngitis/tonsillitis, group A streptococci (1.2 million units 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 intramuscularly [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)
• Yaws, bejel, and pinta (1.2 million units IM x 1)

Pediatric

• Pharyngitis/tonsillitis, group A streptococci: Acute treatment (less than 27 kg = 600,000 units IM x 1; greater than 27 kg = 1.2 million units IM x 1); Chronic carrier treatment (less than 27 kg = 600,000 units IM x 1 in combination with oral rifampin; greater than 27 kg = 1.2 million units IM x 1 in combination with oral rifampin)
• Upper respiratory infection, group A streptococci: (less than 27 kg = 300,000 – 600,000 units IM x 1; greater than 27 kg = 900,000 units IM x 1)
• Secondary prevention of rheumatic fever (less than 27 kg = 600,000 units IM every 3-4 weeks; greater than 27 kg = 1.2 million units IM every 3 to 4 weeks)

Geriatric

• Refer to adult dosing

Infants and Children

• Syphilis: Primary, secondary, and early latent less than 1 year duration (50,000 units/kg/dose IM x 1, maximum 2.4 million units/dose); late latent greater than 1 year duration (50,000 units/kg/dose IM weekly for 3 doses, maximum 2.4 million units/dose)

Renal Impairment

The medication is excreted by renal tubular excretion.

• 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%

Hepatic Impairment

There are no dose adjustments for patients with hepatic impairment.

Seizure Disorders

Use with caution in patients with a seizure disorder, especially in patients with renal impairment, due to a potential increase in the risk of seizures.

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 shown to have any adverse effects on the fetus. However, studies with women who are pregnant are inadequate or not well-controlled and cannot conclusively report harmful effects of penicillin medications on the fetus.

Nursing Mothers

Soluble penicillin G is excreted in breast milk. Caution should be used.

Patients generally tolerate benzathine penicillin well, with pain from the injection being the most common concern. Other adverse events include hypersensitivity reactions. Patients with a previous history of hypersensitivity to penicillins or those with a history of asthma, hay fever, allergies, or urticaria, are at higher risk of hypersensitivity reactions. Hypersensitivity reactions can be serious and/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, diarrhea, and can progress to hemodynamic instability and death. Any previous anaphylactic reaction or serious skin reaction (for example, Steven-Johnson or Toxic Epidermal Necrosis) to any penicillin is a contraindication for use. There have been previous reports that patients with anaphylactic or serious skin reactions from cephalosporins or carbapenems will have a type of cross-reactivity reaction that will also have such serious adverse events when administered any penicillin medication, but these reports are believed to be much lower than previously suspected. 

The other adverse effect is known as a superinfection that 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.[6][7][8]

Benzathine penicillin is contraindicated in patients who have had a previous anaphylactic reaction or serious skin reaction to any penicillin; for example, Steven-Johnson or toxic epidermal necrosis. There have been reports of patients with anaphylactic or serious 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 lower than previously suspected.