Penicillin G benzathine, the benzathine tetrahydrate salt of penicillin G, is a long-acting natural penicillin antibiotic.
Uses
IM penicillin G benzathine is used only for the treatment of mild to moderately severe infections caused by organisms susceptible to low concentrations of penicillin G, for prophylaxis of infections caused by these organisms, or as follow-up therapy to IM or IV penicillin G potassium or sodium. When high concentrations of penicillin G are required, parenteral penicillin G potassium or sodium should be used. For specific information on the uses of penicillin G benzathine, see Uses in the Natural Penicillins General Statement 8:12.16.04.
Dosage and Administration
Administration
Penicillin G benzathine is administered by deep IM injection. Penicillin G benzathine must not be given IV, intravascularly, or intra-arterially. Subcutaneous injection or injection into the fat layer should be avoided since such injections may cause pain and induration. In addition, injection of penicillin G benzathine 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 benzathine in adults should generally be made deeply into the gluteus maximus or into the midlateral thigh. In infants and children, IM injections of the drug should be made preferably into the midlateral muscles of the thigh.
To minimize the possibility of damage to the sciatic nerve, the periphery of the upper outer quadrant of the gluteal regions should be used in infants and small children only when necessary, such as in burn patients.
The deltoid area should be used only if well developed, such as in certain adults and older children, and only with caution to avoid radial nerve injury. 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or any discoloration is present in the syringe, penicillin G benzathine should not be injected; the needle should be withdrawn and the syringe discarded.
A new dose of penicillin G benzathine should be administered at a different site using a new syringe and needle. IM injections of penicillin G benzathine 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.
Pain or induration caused by inadvertent subcutaneous injection or injection into fat layers may be relieved by the application of an ice pack. In children younger than 2 years of age, the penicillin G benzathine dose can be divided and administered at 2 separate sites if necessary. When repeated doses of penicillin G benzathine are given, IM injection sites should be varied.
Dosage
Dosage of penicillin G benzathine is expressed in terms of USP penicillin G units. Streptococcal Infections The usual adult IM dosage of penicillin G benzathine for the treatment mild to moderate upper respiratory tract infections caused by Streptococcus pyogenes (group A b-hemolytic streptococci) is a single dose of 1.2 million units.
The manufacturers recommend that children who weigh less than 27 kg receive a single IM dose of 300,000-600,000 units and that older children receive a single IM dose of 900,000 units.
For the treatment of group A b-hemolytic streptococcal pharyngitis and prevention of initial attacks (primary prevention) of rheumatic fever in children, the Infectious Diseases Society of America (IDSA), American Heart Association (AHA), and American Academy of Pediatrics (AAP) recommend a single IM penicillin G benzathine dose of 600,000 units for individuals weighing 27 kg or less and 1.2 million units for those weighing more than 27 kg.
The single-dose IM penicillin G benzathine regimen may be preferred in patients who are unlikely to complete the recommended 10-day regimen of oral penicillin V potassium and in patients with personal or family histories of rheumatic fever or rheumatic heart disease or other environmental factors (e.g., crowded living conditions) that place them at increased risk for the development of rheumatic fever. Follow-up throat cultures after penicillin G benzathine therapy are necessary only in patients who remain symptomatic, develop recurring symptoms, or have a history of rheumatic fever and are at unusually high risk for recurrence.
Treatment of asymptomatic pharyngeal carriers of group A streptococci generally is not indicated, and these individuals should not receive repeated courses of anti-infective therapy.
However, a second course should be considered in asymptomatic individuals with a personal or family history of rheumatic fever or rheumatic heart disease. In addition, if there is recurrence of signs and symptoms of pharyngitis shortly after the initial regimen is completed (i.e., within a few weeks) and presence of S. pyogenes is documented, retreatment with the original regimen or an alternative anti-infective agent is indicated.
If there are multiple, recurrent episodes of symptomatic pharyngitis within a period of months to years, it may be difficult to determine whether these are true episodes of S. pyogenes infection or whether the patient is a long-term streptococcal pharyngeal carrier who is experiencing repeated episodes of nonstreptococcal pharyngitis (e.g., viral pharyngitis) in whom treatment is not usually indicated. In this situation, the IDSA suggests that symptomatic individuals with multiple, recurrent episodes of documented S. pyogenespharyngitis may receive the usual regimen of IM penicillin G benzathine with or without concomitant oral rifampin (20 mg/kg daily in 2 equally divided doses for 4 days).
Diphtheria
For prevention of diphtheria in asymptomatic, household or intimate contacts of patients with respiratory or cutaneous diphtheria, the US Centers for Disease Control and Prevention (CDC), US Public Health Service Advisory Committee on Immunization Practices (ACIP), and AAP recommend that children younger than 6 years of age or those weighing less than 30 kg receive a single IM penicillin G benzathine dose of 600,000 units and that adults and children 6 years of age or older or those weighing 30 kg or more receive a single IM dose of 1.2 million units.
Household or intimate contacts of patients with diphtheria should receive anti-infective prophylaxis regardless of their immunization status and should be closely monitored for symptoms of diphtheria for 7 days. In addition, contacts who are inadequately immunized against diphtheria (i.e., have previously received fewer than 3 doses of diphtheria toxoid) or whose immunization status is unknown should receive an immediate dose of an age-appropriate diphtheria toxoid preparation and the primary series should be completed according to the recommended schedule.
Contacts who are fully immunized should receive an immediate booster dose of an age-appropriate diphtheria toxoid preparation if it has been 5 years of longer since their last booster dose.
When penicillin G benzathine is used to eliminate the diphtheria carrier state in identified carriers of toxigenic Corynebacterium diphtheriae, adults and children should receive a single IM dose of the drug as specified above for chemoprophylaxis. Follow-up cultures should be obtained at least 2 weeks after treatment of diphtheria carriers; if cultures are positive, a 10-day course of oral erythromycin should be given and additional follow-up cultures obtained.
Syphilis
Primary and Secondary Syphilis
The usual dosage of penicillin G benzathine recommended by the CDC and others for the treatment of primary and secondary syphilis in adults and adolescents is a single IM dose of 2.4 million units.
For the treatment of primary and secondary syphilis in patients with human immunodeficiency virus (HIV) infection, some clinicians suggest that additional doses of 2.4 million units of penicillin G benzathine be given IM once weekly for a total of 3 weeks of therapy.
For pregnant women with primary or secondary syphilis, some clinicians recommend that a second penicillin G benzathine dose of 2.4 million units be administered IM 1 week after the initial dose.
The CDC and AAP recommend that pediatric patients 1 month of age or older with primary or secondary syphilis receive a single IM penicillin G benzathine dose of 50,000 units/kg (up to 2.4 million units). If retreatment of primary or secondary syphilis is necessary and there is no evidence that neurosyphilis is present, many clinicians recommend that the same penicillin G benzathine dosage used for initial treatment be given IM once weekly for 3 successive weeks.
Latent Syphilis and Tertiary Syphilis
For the treatment of early latent syphilis (syphilis of less than 1-year duration), the CDC recommends that adults and adolescents receive a single IM dose of 2.4 million units of penicillin G benzathine.
For the treatment of late latent syphilis, latent syphilis of unknown duration, and tertiary syphilis, the CDC recommends that adults and adolescents receive 2.4 million units of penicillin G benzathine administered IM once weekly for 3 successive weeks (7. million units total).
These regimens can be used to treat early latent syphilis, late latent syphilis, or syphilis of unknown duration in HIV-infected adults and adolescents, provided they have a normal CSF examination. The CDC and AAP recommend that pediatric patients 1 month of age or older with early latent syphilis receive 50,000 units/kg (up to 2.4 million units) of penicillin G benzathine as a single dose and that those with late latent syphilis or latent syphilis of unknown duration receive the drug in a dosage of 50,000 units/kg (up to 2.4 million units) IM once weekly for 3 successive weeks (up to a maximum total dosage of 7.2 million units).
Neurosyphilis
For the treatment of neurosyphilis, the CDC recommends that adults and adolescents receive a regimen of IV penicillin G potassium or sodium (18-24 million units daily for 10-14 days) or, alternatively, IM penicillin G procaine (2.4 million units daily for 10-14 days with oral probenecid). To provide a longer duration of therapy, some clinicians recommend that these regimens be followed by a regimen of IM penicillin G benzathine given in a dosage of 2.4 million units once weekly for up to 3 successive weeks.
Although the manufacturers state that adults can receive 2.4 or 3 million units of penicillin G benzathine IM once weekly for 3 successive weeks for the treatment of neurosyphilis, treatment failures have been reported when this regimen was used alone for the treatment of neurosyphilis. For the treatment of neurosyphilis in pediatric patients, the AAP recommends a regimen of IV penicillin G potassium or sodium (200,000-300,000 units/kg daily for 10-14 days); some clinicians recommend that this regimen be followed by a single IM dose of 50,000 units/kg of penicillin G benzathine (up to 2.4 million units).
Congenital Syphilis
Because diagnosis of congenital syphilis is difficult, treatment decisions for the neonate usually are made based on diagnosis of syphilis in the mother; adequacy of maternal syphilis treatment; presence of clinical, laboratory, or radiographic evidence of syphilis on the neonate; and comparison of maternal nontreponemal serologic titers (at delivery) and titers in the infant.
The CDC recommends that neonates with a normal physical examination and serum quantitative nontreponemal serologic titer the same or less than fourfold the mother’s titer but whose mother was not treated, received inadequate treatment (nonpenicillin regimen, inadequate response to treatment of early syphilis), had undocumented treatment, or received treatment during the last 4 weeks of pregnancy can receive a regimen of IV penicillin G potassium or sodium, IM penicillin G procaine, or IM penicillin G benzathine (a single IM dose of 50,000 units/kg); some clinicians prefer the IV penicillin G regimen if the mother has untreated early syphilis at pregnancy. For neonates with a normal physical examination and a serum nontreponemal serologic titer the same or less than fourfold the mother’s titer and whose mother received adequate treatment during pregnancy (appropriate regimen administered, fourfold decline in nontreponemal test titer for early syphilis or stable or low test titer for late syphilis, no evidence of reinfection or relapse), the CDC recommends a single IM dose of penicillin G benzathine 50,000 units/kg.
While no treatment is required for neonates with a normal physical examination and a serum nontreponemal serologic titer the same or less than fourfold the mother’s titer when maternal treatment was adequate before pregnancy and the mother’s titer remained low and stable before and during pregnancy and at delivery, some clinicians would administer a single IM dose of penicillin G benzathine 50,000 units/kg, especially if adequate follow-up of the infant is not assured.
Although the manufacturers suggest that children younger than 2 years of age with congenital syphilis can receive a single IM penicillin G benzathine dose of 50,000 units/kg, penicillin G benzathine is not recommended for the treatment of known congenital syphilis.
The CDC and AAP recommend a regimen of IV penicillin G potassium or sodium or IM penicillin G procaine for the treatment of neonates with proven or highly probable congenital syphilis. Pediatric patients older than 4 weeks of age who are suspected of having congenital syphilis or who have neurologic involvement and those older than 1 year of age who have late and previously untreated congenital syphilis should receive a regimen of IV penicillin G potassium or sodium (200,000-300,000 units/kg daily for 10 days); some clinicians recommend that this regimen be followed by IM penicillin G benzathine given in a dosage of 50,000 units/kg once weekly for 1-3 weeks.
However, in the older age group, if there are minimal clinical manifestations, normal CSF, and negative CSF VDRL, some clinicians would use IM penicillin G benzathine (50,000 units/kg weekly for 3 weeks) alone. Yaws, Pinta, and Bejel The usual adult dosage of penicillin G benzathine for the treatment of primary and secondary stages of yaws or bejel and all stages of pinta is a single IM dose of 1.2 million units. For the treatment of yaws, some clinicians suggest that adults receive a single IM dose of 2.4 million units, children 6-15 years of age receive a single IM dose of 1.2 million units, and children younger than 6 years of age receive a single IM dose of 300,000 units. However, some clinicians suggest that late latent and tertiary yaws and bejel be treated with 600,000 units of penicillin G benzathine twice weekly or daily for 15-20 doses.
Prevention of Recurrent Rheumatic Fever
For prevention of recurrent rheumatic fever (secondary prophylaxis), the usual dosage of IM penicillin G benzathine for adults or children is 1.2 million units once every 3-4 weeks. The 4-week regimen currently is recommended for most patients in the US. Because of concerns about serum penicillin concentrations declining to subtherapeutic concentrations between the third and fourth weeks in some patients and limited evidence of an increased frequency of prophylactic failure with the 4-week regimen compared with the 3-week regimen in areas with a high risk of rheumatic fever, the AHA and World Health Organization (WHO), state that administration of IM penicillin G benzathine every 3 weeks may be warranted in countries where there is a particularly high incidence of rheumatic fever and in certain high-risk patients. Prevention of recurrent rheumatic fever requires long-term, continuous prophylaxis. (See Uses:
Prevention of Recurrent Rheumatic Fever, in the Natural Penicillins General Statement 8:12.16.04.) Because the risk of recurrence of rheumatic fever appears to be higher with oral prophylaxis than with parenteral prophylaxis, oral agents are more appropriate for patients at lower risk for rheumatic fever recurrence. Some clinicians use IM penicillin G benzathine initially and change to oral prophylaxis (usually with penicillin V potassium) when the patient reaches late adolescence or young adulthood and has remained free of rheumatic attacks for at least 5 years.
Cautions
Adverse Effects
Adverse effects reported with penicillin G benzathine 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.
Precautions and Contraindications
Penicillin G benzathine 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 benzathine, 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 benzathine is contraindicated in patients who are hypersensitive to any penicillin.
Special precaution should be taken to avoid IV, intravascular, or intra-arterial administration of penicillin G benzathine 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 the blood supply occurs at or proximal or distal to the site of injection, an appropriate specialist should be consulted immediately.
For a more complete discussion of these and other precautions associated with the use of penicillin G benzathine, see Cautions: Precautions and Contraindications, in the Natural Penicillins General Statement 8:12.16.04.
Pregnancy and Lactation
Safe use of penicillin G benzathine during pregnancy has not been definitely established. There are no adequate or controlled studies using penicillin G benzathine in pregnant women, and the drug should be used during pregnancy only when clearly needed. Use of penicillin G benzathine is currently included in the US Centers for Disease Control and Prevention (CDC) recommendations for the treatment of syphilis during pregnancy.
Because penicillin G is distributed into milk, penicillin G benzathine should be used with caution in nursing women. Spectrum Based on its spectrum of activity, penicillin G benzathine 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..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 benzathine 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 benzathine 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 procaine or penicillin G potassium or sodium.
Following IM administration of a single dose of penicillin G benzathine in adults, children, or neonates, peak serum concentrations of penicillin G are usually attained in 13-24 hours and are usually detectable for 1-4 weeks depending on the dose. Following IM administration of a single penicillin G benzathine dose of 600,000 units in adults, serum penicillin G concentrations of 0.02 mcg/mL are detectable for 12 days.
Following IM administration of a single penicillin G benzathine dose of 1.2 million units in adults, serum penicillin G concentrations are reportedly 0.15, 0.03, and 0.003 units/mL at 1, 14, and 32 days, respectively, after the dose. Serum penicillin G concentrations of 0.12 mcg/mL may be detectable 14 days after IM administration of a single dose of 2.4 million units of penicillin G benzathine in adults.
In one study in adults who received 2.4 million units of penicillin G benzathine IM once weekly for 3 successive weeks, serum penicillin G concentrations ranged from 0.04-0. units/mL at 7 days after the first dose, 0.06-0. units/mL at 7 days after the second dose, and 0.17-0. units/mL at 7 days after the third dose. In adults receiving 1.2 million units of penicillin G benzathine IM every 4 weeks, mean serum penicillin G concentrations were at least 0.02 mcg/mL for 21 days after a dose; however, at 28 days after a dose, the drug was detectable in serum in only 44% of samples and was at least 0.02 mcg/mL in only 36% of samples.
In one study in children 1.8-10. years of age who received a single IM injection of 600,000 units of penicillin G benzathine if they weighed less than 27 kg or a single IM injection of 1.2 million units of the drug if they weighed more than 27 kg, peak serum penicillin G concentrations occurred 24 hours after the dose and ranged from 0.11-0. mcg/mL. In these patients, serum penicillin G concentrations ranged from 0.04-0. mcg/mL at 1, 2, and 4 hours after the dose and from 0.03-0.13, 0.02-0.09, and 0-0.02 mcg/mL at 5, 10, and 18 days, respectively, after the dose.
Following IM administration of a single dose of 900,000 units of penicillin G benzathine with 300,000 units of penicillin G procaine to children who weighed 11.-22. kg, peak serum penicillin G concentrations occurred 1 hour after the dose and averaged 3.9 mcg/mL. Serum penicillin G concentrations in these patients ranged from 2.5-5.5, 2.5-5.5, 0.7-3.7, and 0.17-0.48 mcg/mL at 1, 2, 4, and 24 hours, respectively, after the dose and from 0.08-0.12, 0.01-0.09, and 0-0.1 mcg/mL at 5, 10, and 18 days, respectively, after the dose.
In one study in neonates who received a single IM penicillin G benzathine dose of 50,000 units/kg, peak serum penicillin G concentrations occurred 24 hours after the dose and ranged from 0.38-2.1 mg/mL; serum penicillin G concentrations ranged from 0.07-0.09 mcg/mL 12 days after the dose. In another study in neonates, IM administration of a single penicillin G benzathine dose of 100,000 units in neonates resulted in serum penicillin G concentrations that ranged from 1.18-3. mcg/mL at 24 hours after the dose and were still detectable 5 days after the dose.
Penicillin G benzathine is more resistant to acid inactivation than other commercially available penicillin G derivatives; however, serum concentrations of penicillin G attained with oral administration of the benzathine salt are reportedly lower and more variable than those attained with the potassium salt of the drug. Following oral administration of 200,000 units of penicillin G benzathine, serum penicillin G concentrations average 0.16 units/mL and decline to undetectable concentrations 8 hours after administration. However, an oral dosage form of penicillin G benzathine is no longer commercially available in the US.
Distribution
Minimal concentrations of penicillin G are generally attained in CSF following IM administration of penicillin G benzathine in patients with inflamed or uninflamed meninges.
The minimum treponemicidal concentration of penicillin G is generally defined as 0.03 units/mL or 0.02 mcg/mL. In one study in adults who received 3.6 million units of penicillin G benzathine IM once weekly for up to 4 weeks, penicillin G was undetectable in the CSF of 12/13 patients in specimens obtained following administration of the last dose. In another study in adults who received 2.4 or 4.8 million units of penicillin G benzathine IM once weekly for 3 successive weeks, CSF penicillin G concentrations were less than 0.03 units/mL in specimens obtained 7 days after the last dose of the drug.
In one study in neonates who received a single IM dose of penicillin G benzathine of 100,000 units/kg, peak CSF penicillin G concentrations occurred 12-24 hours after the dose and ranged from 0.012-0. mcg/mL; however, CSF penicillin G concentrations were less than 0.01 mcg/mL 48 hours after the dose. In one study in children who received a single IM dose of penicillin G benzathine of 600,000 to 1.2 million units, penicillin G concentrations in tonsils were 0.042 mcg/mL or less in specimens obtained 24 hours after the dose; concurrent serum concentrations ranged from 0.03-0.17 mcg/mL.
Elimination
Because penicillin G is slowly absorbed following IM administration of penicillin G benzathine, elimination of penicillin G in urine continues over a prolonged period of time following IM administration of the drug. Penicillin G has been detected in urine for up to 12 weeks after a single IM injection of 1.2 million units of penicillin G benzathine. In one study in children 1.8-10. years of age who received a single IM injection of 600,000 or 1.2 million units of penicillin G benzathine, urinary penicillin G concentrations 30 days after the dose ranged from 0.6-12. mcg/mL.
Following IM administration of a single penicillin G benzathine dose of 50,000 units/kg in neonates, urinary penicillin G concentrations ranged from 4.3-17.2 mcg/mL during the first 4 days after the dose and were 1.4-6 mcg/mL on the 12th day after the dose. 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 benzathine is the benzathine tetrahydrate salt of penicillin G which is prepared by reacting 1 mole of dibenzylethylenediamine diacetate with 2 moles of penicillin G sodium.
Penicillin G benzathine is hydrolyzed in vivo to penicillin G and is frequently referred to as a long-acting, depot, or repository form of penicillin G. Penicillin G benzathine occurs as a white, odorless, crystalline powder. The drug has solubilities of approximately 0.2-0.3 mg/mL in water and 15. mg/mL in alcohol at 25°C. Potency of penicillin G benzathine is generally expressed in terms of USP penicillin G units rather than weight.
Each mg of penicillin G benzathine has a potency of 1090-1272 USP penicillin G units. Commercially available penicillin G benzathine sterile suspension for injection is a suspension of the drug in sterile water for injection. The commercially available suspension has a pH of 5-7.5 and is buffered with sodium citrate. The suspension contains methylparaben and propylparaben as preservatives and also contains povidone, lecithin, and carboxymethylcellulose.
Stability
Commercially available penicillin G benzathine suspension for injection refrigerated 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 benzathine, see the Natural Penicillins General Statement 8:12.16.04.
Preparations
Penicillin G Benzathine Parenteral Suspension, 300,000 units (of penicillin Bicillin® L-A, (with parabens sterile G) per mL and povidone; available as 10- mL vial) Monarch 600,000 units (of penicillin Bicillin® L-A, (with parabens G) per mL and povidone; available as 1- mL and 2-mL Tubex® and as 4-mL disposable syringes) Monarch Permapen®, (with parabens and povidone; available as 2-mL Isoject® disposable syringes) Pfizer Penicillin G Benzathine 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- Procaine 150,000 units (of mL vial) Monarch penicillin G) per mL 300,000 units (of penicillin Bicillin® C-R, (with parabens G) per mL with Penicillin G and povidone; available as 1- Procaine 300,000 units (of mL and 2-mL Tubex® and as 4-mL penicillin G) per mL disposable syringe) Monarch 450,000 units (of penicillin Bicillin® C-R 900/300, (with G) per mL with Penicillin G parabens and povidone; Procaine 150,000 units (of available as 2-mL Tubex®) penicillin G) per mL Monarch