Procaine penicillin is a combination of injectable antibiotic and local anesthetic. Indications for use are quite varied but include the treatment of all stages of syphilis, mild to moderate pneumococcal pneumonia, and as an adjunctive in the treatment of diphtheria along with intramuscular (IM) antitoxin. While procaine penicillin has been described as a treatment for anthrax as well as post-exposure prophylaxis, it is not considered to be the first-choice regimen. Additional indications published include but are not limited to the treatment of infections with Listeria monocytogenes, and various Treponema and Actinomyces species as well as conditions including scarlet fever, rat-bite fever and tonsillitis. Procaine penicillin is not considered to be an appropriate treatment for gonorrhea, and its use in this manner is discouraged by the manufacturer.

The penicillin component of procaine penicillin is a beta-lactam, exerting its bactericidal effects via the inhibition of cell wall synthesis. This activity results from the drug’s binding to naturally occurring proteins in the target organism described as penicillin-binding proteins. These proteins once occupied are then prevented from allowing the completion of the peptidoglycan synthesis essential to the building of the bacterial cell wall. This halting of cell wall production combined with the ongoing activity of native cell wall autolytic enzymes eventually results in cell lysis and subsequent bacterial cell death. Resistance to penicillin primarily occurs in bacteria produced penicillinase. While this resistance phenomenon exists in numerous organisms, it is of note that there is as yet no report of any resistance by Streptococcus pyogenes, in particular.

The procaine component is an amino ester local anesthetic acting on the fast sodium channel to produce local anesthesia. The intent of this anesthetic addition is primarily to ease the pain of IM injection in large enough doses to reach therapeutic concentrations of penicillin.

Procaine penicillin is administered via the deep IM route only. Great care must be taken not to inadvertently inject this drug intravenously (IV) as significant adverse effects can result as described below.

The concentration of drug manufactured is typically 600000 units of penicillin per milliliter with a typical range of dosing in adults from 600000 to 2.4 million units per dose given once per day. When given for post-exposure prophylaxis for anthrax in adults, the regimen is more frequent, every 12 hours. For children, 50000 unit/kilogram is the usual dose without exceeding the adult maximum for a given indication. Depending on the indication, pediatric dosing usually is administered daily or divided to be given twice daily.

The drug typically comes in a preloaded syringe containing either 1 mL or 2 mL of a suspension ready-mixed for administration. In the adult, the preferred site of injection is the upper outer quadrant of the buttock to avoid sciatic nerve toxicity. In infants and small children, the mid-lateral aspect thigh may be preferable to the gluteus. In light of this, the manufacturer recommends avoiding injecting the gluteus altogether in children under two years old. The manufacturer, in all cases, only recommends deep IM injection and varying injection sites with repeat dosing.

With deep IM injection, serum levels of penicillin plateau at four hours and slowly fall over the next 15 to 20 hours, with highest tissue levels seen in the kidneys and lesser levels in the liver, skin, and intestines. Cerebrospinal fluid penetration represents a very small amount of drug. Approximately 60% of penicillin G is bound to serum protein. It then follows that penicillin G is removable via hemodialysis. Renal tubular excretion accounts for 60% to 90% of the excretion of the parenteral dose over 24 to 36 hours. At this time, no discrete recommendations exist for dose adjustment in the setting of chronic renal insufficiency, acute renal injury, or chronic renal failure. If procaine penicillin is suspected of causing impairment of renal function due to interstitial nephritis, discontinuation of the drug and subsequent alternative therapy and indicated consultation is the recommended course of action.

Many of the most deleterious adverse effects of procaine penicillin occur in the setting of inadvertent intravascular administration. These include cardiac conduction disturbance and neurologic sequelae, including tonic-clonic seizure as well as permanent neurovascular damage in the form of conditions such as transverse myelitis and gangrene requiring digital and even proximal extremity amputation. Other adverse events noted have included necrosis and sloughing at the injection site as well as transient psychiatric disturbance; the latter most often observed with the administration of very high doses such as 4.8 million units IM. A syndrome related to procaine known as Hoigne syndrome has been described to include confusion, combativeness, seizures, anxiety, and a sense of impending death. Hoigne symptoms last from 15 to 30 minutes with resolution as the natural course. Treatment centers on symptomatic control.

Other less frequently described adverse events include anaphylactoid reaction, Jarisch-Herxheimer reaction, hemolytic anemia, superinfection at the injection site and interstitial nephritis, and acute generalized exanthematous pustulosis (AGEP). AGEP is a poorly understood condition that has been reported in the timeframe of two to three weeks after the initiation of therapy, resulting in fever and a desquamating rash.

Penicillin gets excreted in breast milk; therefore, appropriate caution is necessary for nursing mothers.

Animal models have shown no evidence of teratogenesis, and penicillin has not been historically observed to have adverse effects on the human fetus. In light of the lack of randomized trials to demonstrate safety, the manufacturer recommends administration of procaine penicillin in pregnancy only if needed.

Contraindications include a history of an allergic reaction to either the penicillin or procaine component or other ester anesthetics. Careful consideration is necessary for patients with a history of carbapenem and/or cephalosporin sensitivity. Caution is also urged in those patients with diarrhea as the administration of penicillin procaine could, as with many broad-spectrum antibiotics, potentially worsen the course of pseudomembranous colitis due to Clostridium difficile.

Large doses of penicillin given to patients with renal impairment have correlations with seizures according to one manufacturer, and clinicians should avoid administration in a patient with a history of both renal impairment and seizures. Caution should still be exercised in those patients with a renal impairment alone as well as with those patients with a history of seizure without renal impairment.

Other considerations include drug interactions with other therapies. In particular procaine penicillin may decrease the efficacy of typhoid vaccine and, when given in the setting of methotrexate therapy, may increase serum concentrations of the latter, leading to potential methotrexate toxicity including hematologic and gastroenterological manifestations. Concurrent administration of probenecid can result in increased serum concentrations of penicillin G and therefore should be approached with caution to avoid toxicity. Tetracycline administration may antagonize the bactericidal effect of penicillin, and thus the manufacturer recommends against the administration of these drugs together.