Penicillin G procaine, the procaine monohydrate salt of penicillin G, is a long-acting natural penicillin antibiotic.
Uses
Penicillin G procaine is used only for the treatment of moderately severe infections caused by organisms susceptible to low concentrations of penicillin G or as follow-up therapy to IM or IV penicillin G potassium or sodium. When high penicillin G concentrations are required, IM or IV penicillin G potassium or sodium should be used. For specific information on the uses of penicillin G procaine, see Uses in the Natural Penicillins General Statement 8:12.16.04.
Dosage and Administration
Administration
Penicillin G procaine is administered by deep IM injection. Penicillin G procaine must not be given IV, intravascularly, or intra-arterially. In addition, injection of penicillin G procaine into or near a nerve must be avoided since permanent neurologic damage may result. Repeated IM injection of the drug into the anterolateral thigh, especially in neonates and infants, should also be avoided since quadriceps femoris fibrosis and atrophy may occur. (See Cautions: Nervous System and Neurovascular Effects, in the Natural Penicillins General Statement 8:12.16.04.) IM injections of penicillin G procaine in adults should generally be made deeply into the gluteus maximus. In infants and children, IM injections of the drug should be given preferably into the midlateral muscles of the thigh.
The plunger of the syringe should be drawn back before IM injection to ensure that the needle is not in a blood vessel. If blood or any discoloration is present in the syringe, penicillin G procaine should not be injected; the needle should be withdrawn and the syringe discarded.
A new dose of penicillin G procaine should be administered at a different site using a new syringe and needle. IM injection of penicillin G procaine should be made at a slow, steady rate to avoid blockage of the needle. Injection of the drug should be discontinued if the patient complains of severe immediate pain at the injection site or if, especially in infants and children, signs or symptoms suggesting the onset of severe pain occur. When repeated doses of penicillin G procaine are given, IM injection sites should be varied.
Dosage
Dosage of penicillin G procaine is expressed in terms of USP penicillin G units. Pediatric Dosage For children older than 1 month of age, the American Academy of Pediatrics (AAP) recommends that penicillin G procaine be given in a dosage of 25,000-50,000 units/kg daily in 1 or 2 daily doses. Although some clinicians state that use of penicillin G procaine in neonates generally is unnecessary since the drug offers no advantages over parenteral penicillin G potassium or sodium in this age group, the AAP and other clinicians state that neonates can receive penicillin G procaine in a dosage of 50,000 units/kg once daily.
Staphylococcal and Streptococcal Infections
For the treatment of infections caused by Streptococcus pyogenes (group A b-hemolytic streptococci) such as moderate to severe upper respiratory tract infections, otitis media, tonsillitis, pharyngitis, erysipelas, scarlet fever, and skin or skin structure infections, the usual adult dosage of penicillin G procaine is 600,000 to 1 million units daily for a minimum of 10 days. Children weighing less than 27 kg can receive 300,000 units daily. The manufacturer states that bacterial endocarditis caused by extremely susceptible strains of group A streptococci may be treated with 600,000 to 1 million units of penicillin G procaine daily; however, penicillin G potassium or sodium generally is used in the treatment of endocarditis.
For the treatment of moderately severe, uncomplicated respiratory tract infections (pneumonia) caused by susceptible S. pneumoniae, the manufacturer recommends that adults receive a penicillin G procaine dosage of 600,000 to 1 million units daily.
The usual adult dosage of penicillin G procaine for the treatment of moderate to severe skin or skin structure infections caused by susceptible nonpenicillinase-producing Staphylococcus is 600,000 to 1 million units daily.
Anthrax
The usual adult dosage of penicillin G procaine for the treatment of cutaneous anthrax is 600,000 to 1 million units daily. Although 5-10 days of anti-infective therapy may be adequate for the treatment for mild, uncomplicated cutaneous anthrax that occurs as the result of naturally occurring or endemic exposures to anthrax, the US Centers for Disease Control and Prevention (CDC) and other experts recommend that therapy be continued for 60 days if cutaneous anthrax occurred as the result of exposure to aerosolized Bacilllus anthracis spores since the possibility of inhalational anthrax would also exist.
When penicillin G procaine is used for postexposure prophylaxis to reduce the incidence or progression of disease following exposure to aerosolized B. anthracis spores in the context of biologic warfare or bioterrorism, adults should receive 1.2 million units every 12 hours and children should receive 25,000 units/kg (maximum 1.2 million units) every 12 hours.
Because of concerns regarding possible penicillin resistance, the initial drugs of choice for postexposure prophylaxis following a suspected or confirmed bioterrorism-related exposure to aerosolized anthrax spores are ciprofloxacin or doxycycline. If exposure is confirmed and in vitro tests indicate that the organism is susceptible to penicillin, consideration can be given to changing the postexposure prophylaxis regimen to a penicillin (e.g., amoxicillin, penicillin V).
Penicillin G procaine also has been recommended for postexposure prophylaxis. Anti-infective prophylaxis should be continued until exposure to B. anthracis has been excluded. If exposure is confirmed, postexposure vaccination with anthrax vaccine (if available) may be indicated in conjunction with prophylaxis. Because of the possible persistence of anthrax spores in lung tissue following an aerosol exposure, the CDC and other experts recommend that anti-infective prophylaxis be continued for 60 days.
Safety data for penicillin G procaine administered at the dosage recommended for prophylaxis of anthrax supports a duration of therapy of 2 weeks or less, and clinicians must consider the risks versus benefits of administering penicillin G procaine for longer than 2 weeks or switching to an appropriate alternative anti-infective.
For additional information on treatment of anthrax and recommendations for postexposure prophylaxis following exposure to anthrax spores, see Anthrax under Uses: Gram-positive Bacterial Infections, in the Natural Penicillins General Statement and see Uses: Anthrax, in Ciprofloxacin 8:12.18.
Diphtheria
When used as an adjunct to diphtheria antitoxin for the treatment of diphtheria, the usual dosage of penicillin G procaine in adults is 300,000-600,000 units daily for 14 days. The CDC recommends a dosage of 300,000 units daily for those weighing 10 kg or less and 600,000 units daily for those weighing more than 10 kg. The AAP recommends that pediatric patients receive a dosage of 25,000-50,000 units/kg daily (maximum 1.2 million units daily) given in 2 divided doses for 14 days.
Patients usually are no longer contagious 48 hours after initiation of anti-infective therapy. Eradication of the organism should be confirmed by 2 consecutive negative cultures following completion of therapy. If penicillin G procaine is used to eliminate the diphtheria carrier state in identified carriers of toxigenic C. diphtheriae, the manufacturer recommends a dosage of 300,000 units daily for 10 days. Follow-up cultures should be obtained at least 2 weeks after completion of therapy; if cultures are positive, a 10-day course of oral erythromycin should be given and additional follow-up cultures obtained. Erysipeloid When penicillin G procaine is used in the treatment of uncomplicated infections caused by Erysipelothrix rhusiopathiae, such as erysipeloid, the usual adult dosage is 600,000 to 1 million units daily. Necrotizing Ulcerative Gingivitis The usual adult dosage of penicillin G procaine for the treatment of necrotizing ulcerative gingivitis (Vincent’s infection, trench mouth, Fusobacterium gingivitis or pharyngitis, Leptotrichia buccalis infection) is 600,000 to 1 million units daily.
Syphilis
The manufacturer states that adults with primary, secondary, or latent syphilis with a negative CSF test for syphilis may receive 600,000 units of penicillin G procaine daily for 8 days and that adults with late or latent syphilis with a positive or no CSF test for syphilis may receive 600,000 units of the drug daily for 10-15 days. However, the CDC states that penicillin G benzathine is the drug of choice for the treatment of primary, secondary, or latent syphilis. Although a regimen of IV penicillin G is the recommended regimen for the treatment of neurosyphilis, the CDC states that adults and adolescents with neurosyphilis may be treated with 2.4 million units of IM penicillin G procaine given once daily for 10-14 days in conjunction with oral probenecid (500 mg every 6 hours) if compliance can be ensured; some clinicians recommend that this regimen be followed by a regimen of IM penicillin G benzathine (2.4 million units once weekly for up to 3 weeks).
For the treatment of congenital syphilis, the CDC and AAP state that symptomatic neonates with proven or presumed congenital syphilis may receive a penicillin G procaine dosage of 50,000 units/kg once daily for 10 days.
The CDC and AAP state that if more than 1 day of therapy is missed, the entire course of therapy should be readministered. The manufacturer states that a penicillin G procaine dosage of 50,000 units/kg daily for 10 days may be used to treat congenital syphilis in children weighing less than 32 kg. Yaws, Pinta, and Bejel The manufacturer states that the usual adult dosage of penicillin G procaine for the treatment of yaws, pinta, or bejel is the same as that of the corresponding stage of syphilis.
Rat-Bite Fever
For the treatment of rat-bite fever caused by Streptobacillus moniliformis (erythema arthriticum epidemicum, Haverhill fever) or Spirillum minus (sodoku), the usual adult dosage of penicillin G procaine is 600,000 to 1 million units daily.
Cautions
Adverse Effects
Adverse effects reported with penicillin G procaine are similar to those reported with other natural penicillins. For information on adverse effects reported with natural penicillins, see Cautions in the Natural Penicillins General Statement 8:12.16.04.
Precautions and Contraindications
Penicillin G procaine shares the toxic potentials of the penicillins, including the risk of hypersensitivity reactions, and the usual precautions of penicillin therapy should be observed. Prior to initiation of therapy with penicillin G procaine, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other drugs.
There is clinical and laboratory evidence of partial cross-allergenicity among penicillins and other b-lactam antibiotics including cephalosporins and cephamycins. Penicillin G procaine is contraindicated in patients who are hypersensitive to any penicillin.
Penicillin G procaine also is contraindicated in patients who are hypersensitive to procaine. A small percentage of the population is hypersensitive to procaine and patients with a history of procaine sensitivity should receive a test dose of procaine hydrochloride prior to administration of penicillin G procaine. To test for procaine sensitivity, 0.1 mL of a 1 or 2% solution of procaine hydrochloride should be injected intradermally; development of erythema or a wheal, flare, or eruption at the injection site indicates procaine sensitivity and the patient should not receive penicillin G procaine. If a hypersensitivity reaction to procaine occurs, it should be treated by usual methods; antihistamines may be beneficial, and barbiturates should be used if seizures occur.
Special precaution should be taken to avoid IV, intravascular, or intra-arterial administration of penicillin G procaine or injection of the drug into or near major peripheral nerves or blood vessels since such injections may produce severe and/or permanent neurovascular damage. (See Cautions: Nervous System and Neurovascular Effects, in the Natural Penicillins General Statement 8:12.16.04.) If evidence of compromise of blood supply occurs at or proximal or distal to the site of injection, an appropriate specialist should be consulted immediately.
Renal and hematologic systems should be evaluated periodically during prolonged therapy with penicillin G procaine, particularly if high dosage is used. In such situations, use of penicillin G procaine for longer than 2 weeks may be associated with an increased risk of neutropenia and an increased incidence of serum sickness-like reactions.
For a more complete discussion of these and other precautions associated with the use of penicillin G procaine, see Cautions: Precautions and Contraindications, in the Natural Penicillins General Statement 8:12.16.04.
Pregnancy and Lactation
Safe use of penicillin G procaine during pregnancy has not been definitely established. There are no adequate or controlled studies using penicillin G procaine in pregnant women, and the drug should be used during pregnancy only when clearly needed. Because penicillin G is distributed into milk, penicillin G procaine should be used with caution in nursing women. Spectrum Based on its spectrum of activity, penicillin G procaine is classified as a natural penicillin. For information on the classification of penicillins based on spectra of activity, see the Preface to the General Statements on Penicillins 8:12.16. For specific information on the spectrum of activity of penicillin G and resistance to the drug, see the sections on Spectrum and on Resistance in the Natural Penicillins General Statement 8:12.16.04.
Pharmacokinetics
For additional information on the absorption, distribution, and elimination of penicillin G, see Pharmacokinetics in the Natural Penicillins General Statement 8:12.16.04.
Absorption
Because penicillin G procaine is relatively insoluble, IM administration of the drug provides a tissue depot from which the drug is slowly absorbed and hydrolyzed to penicillin G. IM administration of penicillin G procaine results in serum concentrations of penicillin G that are generally more prolonged, but lower, than those attained with an equivalent IM dose of penicillin G potassium or sodium.
Following IM administration of a single dose of penicillin G procaine in adults or neonates, peak serum penicillin G concentrations are attained in 1-4 hours and the drug is usually detectable in serum for 1-2 days; however, penicillin G may be detectable in serum for up to 5 days depending on the dose. In general, increasing the dose of penicillin G procaine to more than 600,000 units tends to prolong the duration of penicillin G serum concentrations rather than increase peak serum concentrations.
Following IM administration of a single penicillin G procaine dose of 300,000 units in adults, peak serum penicillin G concentrations are attained within 1-3 hours and average 1.5 units/mL; serum penicillin G concentrations average 0.2 and 0.05 units/mL at 24 and 48 hours, respectively, after the dose. Following IM administration of a single penicillin G procaine dose of 600,000 units in one study in adults, serum penicillin G concentrations averaged 1, 1.6, 1.6, 1.4, 0.8, 0.5, and 0.3 units/mL at 1, 2, 4, 6, 12, 15, and 24 hours, respectively, after the dose.
IM administration of a single penicillin G procaine dose of 1.2 million units in adults results in serum penicillin G concentrations of about 1.95, 2.1, 1.2, 0.5, and 0.1 units/mL at 1, 6, 12, 24, and 48 hours, respectively, after the dose. In one study in neonates younger than 1 week of age with congenital syphilis who received a penicillin G procaine dosage of 50,000 units/kg IM once daily for 7 days, serum penicillin G concentrations averaged 7.4-8.8 mcg/mL 2-12 hours after a dose and 1.5 mcg/mL 24 hours after a dose in neonates younger than 1 week of age. In neonates older than 1 week of age who received the same dosage of penicillin G procaine, serum penicillin G concentrations averaged 5-6 mcg/mL during the first 4 hours after administration of a dose and 0.4 mcg/mL 24 hours after a dose.
In another study in neonates who received a single IM penicillin G procaine dose of 50,000 units/kg, peak serum concentrations of penicillin G occurred 4 hours after the dose and ranged from 7.7-41.9 mcg/mL; serum concentrations of the drug ranged from 0.2-5.1 mcg/mL 24 hours after the dose.
Distribution
Minimal concentrations of penicillin G are generally attained in CSF following IM administration of penicillin G procaine in patients with uninflamed meninges. Higher penicillin G concentrations are attained in CSF when the meninges are inflamed or when oral probenecid is administered concomitantly. The minimum treponemicidal concentration of penicillin G is generally defined as 0.03 units/mL or 0.02 mcg/mL.
In one study, CSF concentrations of penicillin G were undetectable to 0.6% of concurrent serum concentrations in patients receiving 600,000 units of penicillin G procaine IM once daily without probenecid; however, CSF concentrations of the drug were 2.1-6.% of concurrent serum concentrations in patients receiving 600,000 units of the drug IM once daily with concomitant oral probenecid (500 mg every 6 hours). In one study in adults following IM administration of 2.4 million units of penicillin G procaine once daily with oral probenecid (500 mg every 6 hours), CSF concentrations of penicillin G ranged from 0.12-0. mcg/mL in specimens obtained 3-3.5 hours after a dose on the third or fourth day of therapy.
In another study in adults with syphilis who received 2.4 million units of penicillin G procaine IM once daily with oral probenecid (500 mg every 6 hours), CSF penicillin G concentrations ranged from 0.07-1. mcg/mL in specimens obtained 2-10 hours after a dose on the second through ninth day of therapy; concurrent serum penicillin G concentrations ranged from 6.3-7.9 mcg/mL. In one study in neonates younger than 3 days of age who received a single IM penicillin G procaine dose of 10,000 units/kg, penicillin G concentrations in CSF 4 hours after the dose averaged 0.06 mcg/mL and concurrent serum concentrations averaged 6.1 mcg/mL.
IM administration of a single penicillin G procaine dose of 50,000 units/kg in these neonates resulted in CSF concentrations averaging 0.14 mcg/mL 4 hours after the dose and concurrent serum concentrations averaging 13.2 mcg/mL. In another study in neonates who received a single penicillin G procaine dose of 50,000 units/kg, peak CSF concentrations of penicillin G occurred 12 hours after the dose and ranged from 0.09-1.98 mcg/mL; CSF concentrations of the drug 24 hours after the dose ranged from 0.03-0.27 mcg/mL.
Elimination
Because penicillin G is slowly absorbed following IM administration of penicillin G procaine, elimination of penicillin G in urine continues over a prolonged period of time following IM administration of the drug. Renal clearance of penicillin G is delayed in neonates and young infants and in individuals with impaired renal function.
Chemistry and Stability
Chemistry
Penicillin G procaine is the procaine monohydrate salt of penicillin G which is prepared by reacting equimolar amounts of penicillin G sodium or potassium and procaine hydrochloride. Penicillin G procaine is hydrolyzed in vivo to penicillin G and frequently is referred to as a long-acting, depot, or repository form of penicillin G. Penicillin G procaine occurs as white crystals or a white, very fine, crystalline powder.
The drug has solubilities of approximately 4-4.5 mg/mL in water and 3.33 mg/mL in alcohol. Potency of penicillin G procaine generally is expressed in terms of USP penicillin G units rather than weight.
Each mg of penicillin G procaine has a potency of 900-1050 USP penicillin G units. Commercially available penicillin G procaine sterile suspension for injection is a viscous, opaque suspension of the drug in sterile water for injection. The commercially available suspension has a pH of 5-7. and is buffered with sodium citrate. The suspension may contain an excess concentration of procaine hydrochloride not exceeding 2%.
The suspension contains methylparaben and propylparaben as preservatives. The suspension also contains povidone, lecithin, and carboxymethylcellulose and may contain sodium formaldehyde sulfoxylate, sorbitol, or phenol.
Stability
Commercially available penicillin G procaine suspension for injection should be stored at 2-8°C; freezing should be avoided. For further information on chemistry and stability, mechanism of action, spectrum, resistance, pharmacokinetics, uses, cautions, drug interactions, laboratory test interferences, and dosage and administration of penicillin G procaine, see the Natural Penicillins General Statement 8:12.16.04.
Preparations
Penicillin G Procaine Parenteral Suspension, 600,000 units (of penicillin Wycillin®, (with parabens and sterile G) per mL povidone; available as 1-mL and 2-mL Tubex®) Monarch Penicillin G Procaine Combinations Parenteral Suspension, 150,000 units (of penicillin Bicillin® C-R, (with parabens sterile G) per mL with Penicillin G and povidone; available as 10- Benzathine 150,000 units (of mL vial) Monarch penicillin G) per mL 150,000 units (of penicillin Bicillin® C-R 900/300, (with G) per mL with Penicillin G parabens and povidone; Benzathine 450,000 units (of available as 2-mL Tubex®) penicillin G) per mL Monarch 300,000 units (of penicillin Bicillin® C-R, (with parabens G) per mL with Penicillin G and povidone; available as 1- Benzathine 300,000 units (of mL and 2-mL Tubex® and as 4-mL penicillin G) per mL disposable syringe) Monarch