Continuing Education Activity

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. This activity outlines the indications, mechanism of action, administration, adverse effects, and contraindications when using benzathine penicillin.

Objectives:

• Identify the approved indications for benzathine penicillin.
• Summarize the mechanism of action of benzathine penicillin.
• Review the potential side effects of benzathine penicillin.
• Explain interprofessional team strategies for improving care coordination and communication to advance appropriate clinical outcomes with benzathine penicillin leading to optimal patient outcomes.

Indications

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

Mechanism of Action

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 cell wall lysis, subsequent destruction of the bacterial cell, and bacterial cellular death.

Administration

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 two 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. Therefore, the antimicrobial is slowly released from the injection site and hydrolyzed to penicillin G. Due to the slow absorption and the hydrolysis, the concentration of the drug in the blood remains 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 should be stored in a refrigerator from 36 to 46 degrees Fahrenheit (2 to 8 degrees Celsius) and 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 four 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 one year (2.4 million units IM x 1, may repeat dose x 1 after one week in pregnant patients); latent greater than one year (2.4 million units IM weekly for three 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

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.

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 pregnant women 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. Clinicians should exercise caution in this patient population.[6]

Adverse Effects

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, and 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 severe 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.[7][8][9]

Contraindications

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 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.

Monitoring

Observe for signs and symptoms of hypersensitivity reactions, including anaphylaxis. Another concern which prescribers and other healthcare team members need to monitor is a lack of therapeutic response, which could be a sign of superinfection.[10]

Toxicity

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 healthcare team members, including the primary care provider, internist, infectious disease expert, nurse practitioner, or physicians assistant. While the drug is relatively safe, it is crucial to observe the patient for an allergic reaction. 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, advise the patient to be sure and take the entire course of medication and not stop if they begin to feel better, and be available for questions, informing the nurse or prescribing clinician of any adverse events or signs of therapeutic failure. In this way, all interprofessional team members can play a role in successful therapeutic patient outcomes with minimal adverse events.