VA Class:AM110

AHFS Class:

• Natural Penicillins 8:12.16.04

Generic Name(s):

• Penicillin G Benzathine

Chemical Name:

• [2 S -(2α,5α,6β)]-3,3-Dimethyl-7-oxo-6-[(phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid compd. with N , N '-bis(phenylmethyl)-1,2-ethanediamine (2:1) tetrahydrate

Molecular Formula:

• (C₁₆H₁₈N₂O₄S)₂•C₁₆H₂₀N₂•4H₂O

Penicillin G benzathine, a natural penicillin, is a β-lactam antibiotic.10,61 The drug is the benzathine tetrahydrate salt of penicillin G and is a long-acting formulation of penicillin G.10,61

Penicillin G benzathine is used only for the treatment of mild to moderately severe infections caused by organisms that are susceptible to the low, prolonged concentrations of penicillin G provided by IM penicillin G benzathine2,3 and for prophylaxis of certain infections caused by these organisms.2,3 When high, sustained concentrations of penicillin G are required for the treatment of severe infections, parenteral penicillin G potassium or sodium should be used.3,4,5,8,9,10,11,61,197

The fixed combinations of penicillin G benzathine and penicillin G procaine are used for the treatment of moderately severe to severe infections caused by susceptible streptococci (e.g., upper respiratory tract infections, scarlet fever, erysipelas, skin and skin structure infections).4,5 The fixed combinations should not be used for initial treatment of severe pneumococcal infections, including pneumonia, empyema, bacteremia, pericarditis, meningitis, peritonitis, or arthritis.4,5 In addition, fixed combinations of penicillin G benzathine and penicillin G procaine should not be used for the treatment of syphilis, yaws, bejel, pinta, or gonorrhea.4,5

For additional information on the uses of penicillin G benzathine, see Uses in the Natural Penicillins General Statement 8:12.16.04.

Pharyngitis and Tonsillitis

IM penicillin G benzathine is a drug of choice for the treatment of pharyngitis and tonsillitis caused by Streptococcus pyogenes (group A β-hemolytic streptococci; GAS) and prevention of initial attacks (primary prevention) of rheumatic fever.292,375,580

Selection of an anti-infective for the treatment of S. pyogenes pharyngitis and tonsillitis should be based on the drug's spectrum of activity, bacteriologic and clinical efficacy, potential adverse effects, ease of administration, patient compliance, and cost.292,375,580 No regimen has been found to date that effectively eradicates group A β-hemolytic streptococci in 100% of patients.375

Because the drugs have a narrow spectrum of activity, are inexpensive, and generally are effective with a low frequency of adverse effects, the American Academy of Pediatrics (AAP),292 Infectious Diseases Society of America (IDSA),580 and American Heart Association (AHA)375 recommend a penicillin regimen (i.e., 10 days of oral penicillin V or oral amoxicillin or a single dose of IM penicillin G benzathine) as the treatment of choice for S. pyogenes pharyngitis and tonsillitis.292,375,580 Other anti-infectives (narrow-spectrum oral cephalosporins, oral macrolides, oral clindamycin) are recommended as alternatives in penicillin-allergic patients.292,375,580

Experts state that the single-dose IM penicillin G benzathine regimen may be the preferred regimen in patients who are unlikely to complete the recommended 10-day regimen of oral penicillin V potassium or amoxicillin292,375,580 and in patients with a personal or family history of rheumatic fever or rheumatic heart disease or with other environmental factors (e.g., crowded living conditions) that place them at increased risk for development of rheumatic fever.375

If signs and symptoms of pharyngitis recur shortly after initial treatment and presence of S. pyogenes is documented, retreatment with the original or an alternative anti-infective is recommended.292,375,580 Initial treatment failures may occur more frequently with oral penicillins than with IM penicillin G benzathine because of poor adherence to the oral regimen.292,375,580 Alternative regimens recommended for retreatment include a narrow-spectrum oral cephalosporin, oral clindamycin, oral fixed combination of amoxicillin and clavulanate, oral macrolide, or IM penicillin G benzathine.292,375,580

If there are multiple, recurrent episodes of symptomatic pharyngitis within a period of several 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 pharyngeal carrier of S. pyogenes who is experiencing repeated episodes of nonstreptococcal (e.g., viral) pharyngitis.292,375,580

Treatment of asymptomatic chronic pharyngeal carriers of S. pyogenes is not usually indicated and these individuals should not receive repeated courses of anti-infective therapy.292,375,580 However, eradication of the carrier state may be desirable in certain situations (e.g., during a community outbreak of acute rheumatic fever, acute poststreptococcal glomerulonephritis, or invasive S. pyogenes infections; during an outbreak of S. pyogenes pharyngitis in a closed or partially closed community; when multiple episodes of documented symptomatic S. pyogenes pharyngitis are occurring within a family for many weeks despite appropriate treatment; when there is a personal or family history of acute rheumatic fever).292,580 In such situations, recommended regimens include oral clindamycin, oral fixed combination of amoxicillin and clavulanate, or oral rifampin used in conjunction with either IM penicillin G benzathine or oral penicillin V.292,580

Prevention of Rheumatic Fever Recurrence

IM penicillin G benzathine is used for prevention of recurrent attacks of rheumatic fever (secondary prophylaxis) in individuals who have had a previous attack of rheumatic fever.292,375

IM penicillin G benzathine generally is considered the drug of choice for secondary prophylaxis of rheumatic fever because it ensures compliance;292,375 alternatives include oral penicillin V or oral sulfadiazine.292,375 Sulfadiazine is recommended when hypersensitivity precludes the use of a penicillin; however, a macrolide (azithromycin, clarithromycin, erythromycin) should be used in patients allergic to penicillins and sulfonamides.375 Even with optimal patient adherence, the risk of recurrence of rheumatic fever is higher in individuals receiving an oral prophylaxis regimen than in those receiving IM penicillin G benzathine.375

AHA and AAP recommend long-term (continuous) secondary prophylaxis in patients who have been treated for documented acute rheumatic fever (even if manifested solely by Sydenham chorea) and in those with evidence of rheumatic heart disease (even after prosthetic valve replacement).292,375

Prophylaxis should be initiated as soon as the diagnosis of rheumatic fever or rheumatic heart disease is made,292,375 although patients with acute rheumatic fever should first receive the usually recommended anti-infective treatment for S. pyogenes pharyngitis and tonsillitis (see Uses: Pharyngitis and Tonsillitis).375

Syphilis

IM penicillin G benzathine is used for the treatment of syphilis.2,3,61,344,345,350,440,441

The US Centers for Disease Control and Prevention (CDC) and other experts state that IM penicillin G benzathine is the drug of choice for the treatment of primary syphilis (i.e., ulcer or chancre at infection site), secondary syphilis (i.e., manifestations that include, but are not limited to, rash, mucocutaneous lesions, and lymphadenopathy), and tertiary syphilis (i.e., cardiac syphilis, gummatous lesions, tabes dorsalis, and general paresis) in adults, adolescents, and children.344,345,350,440,441

IM penicillin G benzathine also is the drug of choice for the treatment of latent syphilis (i.e., detected by serologic testing but lacking clinical manifestations), including both early latent syphilis (latent syphilis acquired within the preceding year) and late latent syphilis (i.e., all other cases of latent syphilis or syphilis of unknown duration) in all age groups.344,345,350,440,441

For the treatment of neurosyphilis and otic or ocular syphilis, CDC and other experts state that IV penicillin G potassium or sodium is the drug of choice and IM penicillin G procaine (with oral probenecid) is an alternative if compliance can be ensured.344,345,440,441

For the treatment of congenital syphilis, CDC recommends IV penicillin G potassium or sodium or IM penicillin G procaine in neonates with proven or highly probable congenital syphilis (i.e., abnormal physical examination consistent with congenital syphilis, serum quantitative nontreponemal serologic titer fourfold higher than the mother's titer, or positive darkfield test or polymerase chain reaction [PCR] of lesions or body fluids).344 CDC recommends IV penicillin G potassium or sodium, IM penicillin G procaine, or IM penicillin G benzathine in neonates with possible congenital syphilis (i.e., normal physical examination and serum quantitative nontreponemal serologic titer no more than fourfold higher than the mother's titer and the mother received a recommended treatment regimen less than 4 weeks before delivery; the mother was not treated or was inadequately treated, including treatment with erythromycin or any regimen not included in CDC recommendations; or there is no documentation that the mother received treatment).344

Neonates with human immunodeficiency virus (HIV) infection who have congenital syphilis and HIV-infected children, adolescents, and adults who have neurosyphilis or primary, secondary, early latent, late latent, or tertiary syphilis should receive the same treatment regimens as those without HIV infection.344,440,441 Available data indicate that additional treatment doses of IM penicillin G benzathine do not enhance efficacy, including in HIV-infected patients.344 Because serologic nonresponse and neurologic complications may be more frequent in HIV-infected individuals, close follow-up is essential in those coinfected with syphilis and HIV.344,440 In addition, careful neurologic examinations are indicated in all HIV-infected patients coinfected with syphilis.440

Limited data support the use of certain alternatives to IM penicillin G benzathine for treatment of primary or secondary syphilis in patients with penicillin hypersensitivity (e.g., doxycycline, tetracycline);344,350 however, if compliance with alternative regimens or follow-up cannot be ensured, CDC recommends desensitization and treatment with IM penicillin G benzathine.344 Some experts state that efficacy of alternatives to IM penicillin G benzathine for the treatment of early syphilis in HIV-infected individuals has not been well studied and use of alternatives in such patients should be undertaken only with close clinical and serologic monitoring.440

There are no proven alternatives to penicillin G for the treatment of congenital syphilis in infants and children with known or suspected penicillin hypersensitivity and no proven alternatives to penicillin G for the treatment of any stage of syphilis in pregnant women with penicillin hypersensitivity;344 therefore, CDC recommends desensitization and treatment with the appropriate penicillin G preparation.344

Fixed combinations of penicillin G benzathine and penicillin G procaine (Bicillin ^®C-R, Bicillin ^®C-R 900/300) should not be used for the treatment of any form of syphilis; 4,5,17,18,344 inadvertent use of one of these fixed-combination preparations may not provide the sustained serum concentrations of penicillin G required for treatment of syphilis and could increase the risk of treatment failure and neurosyphilis, especially in HIV-infected patients.18

For additional information regarding treatment of syphilis, the current CDC sexually transmitted diseases treatment guidelines available at [Web] should be consulted.344

Administration

Penicillin G benzathine2,3 and fixed combinations containing penicillin G benzathine and penicillin G procaine4,5 are administered only by deep IM injection.2,3,4,5

Special precaution should be taken to avoid inadvertent intravascular or intra-arterial administration of penicillin G benzathine or fixed combinations of penicillin G benzathine and penicillin G procaine or injection into or near major peripheral nerves or blood vessels because this may result in severe and/or permanent neurovascular damage.2,3,4,5 (See Cautions: Adverse Effects.)

Penicillin G benzathine and fixed combinations containing penicillin G benzathine and penicillin G procaine must not be given IV or admixed with IV solutions because inadvertent IV administration of penicillin G benzathine has been associated with cardiorespiratory arrest and death.2,4,5

IM Injection

Penicillin G benzathine and fixed combinations containing penicillin G benzathine and penicillin G procaine are provided in prefilled syringes and the appropriate dose should be administered undiluted according to the manufacturer's directions.2,3,4,5

In adults, IM injections of penicillin G benzathine or fixed combinations of penicillin G benzathine and penicillin G procaine generally should be made deeply into the gluteus maximus (upper outer quadrant of the buttock) or into the midlateral thigh.2,3,4,5 In neonates, infants, and small children, IM injections of these preparations should be given preferably into the midlateral muscles of the thigh.2,3,4,5

To minimize the possibility of damage to the sciatic nerve, one manufacturer of penicillin G benzathine recommends that the periphery of the upper outer quadrant of the gluteal regions be used in infants and small children only when necessary (e.g., in burn patients) and recommends that the deltoid area be used only if well developed, such as in certain adults and older children, and only with caution to avoid radial nerve injury.3 This manufacturer also suggests that the penicillin G benzathine dose can be divided and administered at 2 separate sites if necessary in children younger than 2 years of age.3

IM injections may be less painful if penicillin G benzathine is warmed to room temperature before administration.292,375

IM injections of penicillin G benzathine or fixed combinations of penicillin G benzathine and penicillin G procaine should be made at a slow, steady rate to avoid blockage of the needle.2,4,5

When the fixed combination of penicillin G benzathine and penicillin G procaine (Bicillin^® C-R) is used, the manufacturer states that the dose usually is given at a single session using multiple IM sites; alternatively, if compliance regarding the return visit is ensured, the total dose can be divided and half given on day 1 and half on day 3.5

When repeated doses are given, IM injection sites should be rotated.2,3,4,5 Repeated IM injection into the anterolateral thigh, especially in neonates and infants, should be avoided because quadriceps femoris fibrosis and atrophy have been reported.2,4,5

Dosage

Dosage of penicillin G benzathine usually is expressed in terms of penicillin G units,2,3 but also has been expressed as mg of penicillin G.61

Dosage of the fixed combinations containing penicillin G benzathine and penicillin G procaine (Bicillin^® C-R, Bicillin^® C-R 900/300) usually is expressed in terms of the total (sum) of penicillin G units of penicillin G benzathine and penicillin G units of penicillin G procaine.4,5

Pediatric Dosage

General Pediatric Dosage

The American Academy of Pediatrics (AAP) states that the usual dosage of IM penicillin G benzathine for the treatment of mild to moderate infections in pediatric patients beyond the neonatal period is a single dose of 300,000-600,000 units in those weighing less than 27 kg or a single dose of 900,000 units in those weighing 27 kg or more.292 AAP states that IM penicillin G benzathine is inappropriate for the treatment of severe infections.292

If the fixed combination of penicillin G benzathine and penicillin G procaine (Bicillin^® C-R) is used in pediatric patients beyond the neonatal period, AAP recommends a single IM dose of 600,000 penicillin G units in those weighing less than 14 kg and a single IM dose of 900,000 to 1.2 million penicillin G units in those weighing 14-27 kg.292 If this fixed-combination preparation is used in those weighing 27 kg or more, AAP recommends a single dose of 2.4 million penicillin G units.292

Pharyngitis and Tonsillitis

For the treatment of pharyngitis or tonsillitis caused by Streptococcus pyogenes (group A β-hemolytic streptococci; GAS) and prevention of initial attacks (primary prevention) of rheumatic fever in children, AAP, Infectious Diseases Society of America (IDSA), and American Heart Association (AHA) recommend that IM penicillin G benzathine be given as a single dose of 600,000 units in those weighing less than 27 kg and a single dose of 1.2 million units in those weighing 27 kg or more.292,375,580

The manufacturers recommend a single IM penicillin G benzathine dose of 300,000-600,000 units in children weighing less than 27 kg2 and a single dose of 900,000 units in older children for the treatment of S. pyogenes pharyngitis.2,3

Although anti-infective treatment is not recommended for most individuals identified as chronic pharyngeal carriers of S. pyogenes (see Uses: Pharyngitis and Tonsillitis), IDSA states that a single IM penicillin G benzathine dose of 600,000 units in those weighing less than 27 kg or 1.2 million units in those weighing 27 kg or more given in conjunction with oral rifampin (20 mg/kg daily given in 2 doses [up to 600 mg daily] for 4 days) is an option when eradication of the carrier state is desirable.580

Streptococcal Infections

If IM penicillin G benzathine is used for the treatment of mild to moderate infections of the upper respiratory tract caused by susceptible S. pyogenes , one manufacturer recommends a single dose of 300,000-600,000 units in children weighing less than 27 kg and 900,000 units in older pediatric patients.2

If the fixed combination of penicillin G benzathine and penicillin G procaine (Bicillin^® C-R) is used for the treatment of moderately severe to severe infections caused by susceptible S. pyogenes (e.g., upper respiratory tract infections, scarlet fever, erysipelas, skin and skin structure infections), the manufacturer recommends that children weighing less than 13.6 kg receive a single IM dose of 600,000 penicillin G units, those weighing 13.6-27.2 kg receive a single IM dose of 900,000 to 1.2 million penicillin G units, and those weighing more than 27.2 kg receive a single IM dose of 2.4 million penicillin G units.5 If this fixed-combination preparation is used for the treatment of moderately severe infections caused by susceptible S. pneumoniae (pneumonia, otitis media), the manufacturer recommends that pediatric patients receive an IM dose of 600,000 penicillin G units once every 2 or 3 days until the patient has been afebrile for 48 hours.5 Other penicillins are recommended for severe S. pneumoniae infections (e.g., pneumonia, empyema, bacteremia, pericarditis, meningitis, peritonitis, arthritis).5

If the fixed combination of penicillin G benzathine and penicillin G procaine (Bicillin^® C-R 900/300) is used for the treatment of moderately severe to severe infections caused by susceptible S. pyogenes (e.g., upper respiratory tract infections, scarlet fever, erysipelas, skin and skin structure infections), the manufacturer states that a single IM dose of 1.2 million penicillin G units usually is sufficient in pediatric patients.4 If this fixed-combination preparation is used for the treatment of moderately severe infections caused by susceptible S. pneumoniae (pneumonia, otitis media), the manufacturer recommends that pediatric patients receive an IM dose of 1.2 million penicillin G units once every 2 or 3 days until the patient has been afebrile for 48 hours.4 Other penicillins are recommended for severe S. pneumoniae infections (e.g., pneumonia, empyema, bacteremia, pericarditis, meningitis, peritonitis, arthritis).4

Diphtheria

If IM penicillin G benzathine is used for prevention of diphtheria† in asymptomatic household or close contacts of patients with respiratory or cutaneous diphtheria caused by Corynebacterium diphtheriae , the US Centers for Disease Control and Prevention (CDC) and AAP recommend that children younger than 6 years of age or those weighing less than 30 kg receive a single dose of 600,000 units and that children 6 years of age or older or those weighing 30 kg or more receive a single dose of 1.2 million units.166,292 Household or close 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.292 Contacts who are inadequately immunized against diphtheria or whose immunization status is unknown should receive an immediate dose of an age-appropriate preparation containing diphtheria toxoid adsorbed and the primary series should be completed according to the recommended schedule.292 Contacts who are fully immunized should receive an immediate booster dose of an age-appropriate preparation containing diphtheria toxoid adsorbed if it has been 5 years or longer since their last booster dose.166,292

When IM penicillin G benzathine is used to eliminate the diphtheria carrier state† in identified carriers of toxigenic C. diphtheriae , CDC and AAP recommend that children younger than 6 years of age or those weighing less than 30 kg receive a single dose of 600,000 units and that children 6 years of age or older or those weighing 30 kg or more receive a single dose of 1.2 million units.166,292 Follow-up cultures should be obtained at least 2 weeks after treatment of diphtheria carriers;166 if cultures are positive, a 10-day course of oral erythromycin should be given and additional follow-up cultures obtained.166,292

Syphilis

If IM penicillin G benzathine is used for the treatment of possible congenital syphilis or when congenital syphilis is less likely (see Uses: Syphilis), CDC and the manufacturers recommend a single dose of 50,000 units/kg.2,3,344 Neonates with proven or highly probable congenital syphilis (see Uses: Syphilis) should receive a 10-day regimen of IV penicillin G potassium or sodium or IM penicillin G procaine.344

In infants and children 1 month of age or older with reactive serologic tests for syphilis but no clinical manifestation of congenital syphilis and a normal evaluation (including CSF examination), CDC states that treatment with IM penicillin G benzathine given in a dosage of 50,000 units/kg (up to 2.4 million units) once weekly for up to 3 weeks can be considered.344 If a 10-day regimen of IV penicillin G potassium or sodium is used in such patients, a single dose of IM penicillin G benzathine (50,000 units/kg) may be considered after completion of the IV regimen.344

For the treatment of primary, secondary, or early latent syphilis in infants and children 1 month of age or older, CDC and others recommend that IM penicillin G benzathine be given as a single dose of 50,000 units/kg (up to 2.4 million units).344,441

For the treatment of late latent syphilis in infants and children 1 month of age or older, CDC and others recommend that IM penicillin G benzathine be given in a dosage of 50,000 units/kg (up to 2.4 million units) administered once weekly for 3 consecutive weeks (up to a maximum total dosage of 7.2 million units).344,441

CDC recommends that treatment of syphilis diagnosed in infants and children 1 month of age or older should be managed by a pediatric infectious disease specialist and that CSF should be examined in those with latent syphilis.344,344

In adolescents 10-19 years of age, some experts state that those with early syphilis (primary, secondary, or early latent syphilis) should receive a single IM penicillin G benzathine dose of 2.4 million units and that those with late latent syphilis or syphilis of unknown duration should receive IM penicillin G benzathine in a dosage of 2.4 million units once weekly for 3 consecutive weeks.350 The interval between consecutive doses of IM penicillin G benzathine should not exceed 14 days.350

Neonates with human immunodeficiency virus (HIV) infection who have congenital syphilis and HIV-infected children and adolescents with any stage of syphilis should receive the same treatment regimens recommended for those without HIV infection.344,441

Fixed combinations of penicillin G benzathine and penicillin G procaine (Bicillin ^®C-R, Bicillin ^®C-R 900/300) should not be used for the treatment of any form of syphilis. 4,5,17,18,344

Yaws, Pinta, and Bejel

For the treatment of yaws, pinta, and bejel in children, IM penicillin G benzathine has been given as a single dose of 600,000 units in those younger than 10 years of age or 1.2 million units in those 10 years of age or older.35,36,676,678 A single IM dose of 50,000 units/kg (up to 2.4 million units) also has been used for the treatment of yaws in children.679

Fixed combinations of penicillin G benzathine and penicillin G procaine (Bicillin ^®C-R, Bicillin ^®C-R 900/300) should not be used for the treatment of yaws, pinta, or bejel. 4,5

Prevention of Rheumatic Fever Recurrence

For prevention of recurrent rheumatic fever (secondary prophylaxis), AAP and AHA state that the usual dosage of IM penicillin G benzathine is 600,000 units once every 4 weeks in children weighing 27 kg or less and 1.2 million units once every 4 weeks in those weighing more than 27 kg.292,375 The manufacturers recommend that penicillin G benzathine be given in a dosage of 1.2 million units once monthly or 600,000 units once every 2 weeks for such prophylaxis.2,3

AAP and AHA state that an IM penicillin G benzathine regimen that uses a 4-week dosing interval seems adequate and is recommended for most patients in the US, but a 3-week dosing interval may be warranted and is recommended when there is a particularly high risk of rheumatic fever (e.g., recurrent acute rheumatic fever despite adherence to a 4-week regimen).292,375 There is some evidence that serum penicillin concentrations may decline to subtherapeutic concentrations before the fourth week in some patients37,323,375 and there is limited evidence of an increased frequency of prophylactic failure with a 4-week interval compared with a 3-week interval in areas with a high risk of rheumatic fever.37,38

Prevention of recurrent rheumatic fever requires long-term, continuous prophylaxis.292,375 (See Table 1.) Some clinicians use IM penicillin G benzathine initially and change to oral prophylaxis (usually oral penicillin V) when the patient reaches late adolescence or young adulthood and has remained free of rheumatic attacks for at least 5 years.375

Adult Dosage

Pharyngitis and Tonsillitis

For the treatment of pharyngitis or tonsillitis caused by S. pyogenes (group A β-hemolytic streptococci; GAS) and prevention of initial attacks (primary prevention) of rheumatic fever, the usual adult dosage of penicillin G benzathine is a single IM dose of 1.2 million units.2,3,375,580

Although anti-infective treatment is not recommended for most individuals identified as chronic pharyngeal carriers of S. pyogenes (see Uses: Pharyngitis and Tonsilitis), IDSA states that a single IM penicillin G benzathine dose of 600,000 units in those weighing less than 27 kg or 1.2 million units in those weighing 27 kg or more given in conjunction with oral rifampin (20 mg/kg daily given in 2 doses [up to 600 mg daily] for 4 days) is an option when eradication of the carrier state is desirable.580

Streptococcal Infections

If IM penicillin G benzathine is used for the treatment of mild to moderate upper respiratory tract infections caused by susceptible S. pyogenes (group A β-hemolytic streptococci; GAS), adults should receive a single dose of 1.2 million units.2,3

If the fixed combination of penicillin G benzathine and penicillin G procaine (Bicillin^® C-R) is used for the treatment of moderately severe to severe infections caused by susceptible S. pyogenes (e.g., upper respiratory tract infections, scarlet fever, erysipelas, skin and skin structure infections), the manufacturer recommends that adults receive a single IM dose of 2.4 million penicillin G units.5 If this fixed-combination preparation is used for the treatment of moderately severe infections caused by susceptible S. pneumoniae (pneumonia, otitis media) in adults, the manufacturer recommends an IM dose of 1.2 million penicillin G units once every 2 or 3 days until the patient has been afebrile for 48 hours.5 Other penicillins are recommended for severe S. pneumoniae infections (e.g., pneumonia, empyema, bacteremia, pericarditis, meningitis, peritonitis, arthritis).5

Diphtheria

If IM penicillin G benzathine is used for prevention of diphtheria† in asymptomatic household or close contacts of patients with respiratory or cutaneous diphtheria, CDC recommends that adults receive a single dose of 1.2 million units.166 Household or close 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.166,292 Contacts who are inadequately immunized against diphtheria or whose immunization status is unknown should receive an immediate dose of an age-appropriate preparation containing diphtheria toxoid adsorbed and the primary series should be completed according to the recommended schedule.292 Contacts who are fully immunized should receive an immediate booster dose of an age-appropriate preparation containing diphtheria toxoid adsorbed if it has been 5 years or longer since their last booster dose.166,292

When IM penicillin G benzathine is used to eliminate the diphtheria carrier state† in identified carriers of toxigenic C. diphtheriae , adults should receive a single dose of 1.2 million units.166 Follow-up cultures should be obtained at least 2 weeks after treatment of diphtheria carriers;166 if cultures are positive, a 10-day course of oral erythromycin should be given and additional follow-up cultures obtained.166,292

Syphilis

For the treatment of primary, secondary, or early latent syphilis in adults, CDC, the manufacturers, and others recommend that IM penicillin G benzathine be given as a single dose of 2.4 million units.2,3,344,345,350,440 For pregnant women with primary, secondary, or early latent syphilis, some clinicians recommend that a second IM penicillin G benzathine dose of 2.4 million units be given 1 week after the initial dose.344,440 If retreatment of primary, secondary, or early latent syphilis is necessary and there is no evidence that neurosyphilis is present, CDC and others recommend that adults receive IM penicillin G benzathine in a dosage of 2.4 million units once weekly for 3 consecutive weeks.344,440

For the treatment of late latent syphilis, latent syphilis of unknown duration, or tertiary syphilis, CDC and others recommend that adults receive IM penicillin G benzathine in a dosage of 2.4 million units once weekly for 3 consecutive weeks (total dosage 7.2 million units).2,344,345,350,440 The interval between consecutive doses of IM penicillin G benzathine should not exceed 14 days.350

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,2,3 treatment failures have been reported when penicillin G benzathine was used alone for the treatment of neurosyphilis.702,874 CDC and others state that IV penicillin G potassium or sodium is the drug of choice for the treatment of neurosyphilis and IM penicillin G procaine (with oral probenecid) is an alternative if compliance can be ensured.344,345,440 Some clinicians recommend that the IV penicillin G potassium or sodium regimen or IM penicillin G procaine regimen be followed by a regimen of IM penicillin G benzathine (2.4 million units once weekly for up to 3 weeks).344

HIV-infected adults with any stage of syphilis should receive the same treatment regimens recommended for those without HIV infection.344,440

Fixed combinations of penicillin G benzathine and penicillin G procaine (Bicillin ^®C-R, Bicillin ^®C-R 900/300) should not be used for the treatment of any form of syphilis. 4,5,17,18,344

Yaws, Pinta, and Bejel

For the treatment of yaws, pinta, and bejel in adults, IM penicillin G benzathine has been given as a single dose of 1.2 million units.2,3,35,36,676,678 A single IM dose of 2.4 million units also has been used for the treatment of yaws.61,674,675

Fixed combinations of penicillin G benzathine and penicillin G procaine (Bicillin ^®C-R, Bicillin ^®C-R 900/300) should not be used for the treatment of yaws, pinta, or bejel. 4,5

Prevention of Rheumatic Fever Recurrence

For prevention of rheumatic fever recurrence (secondary prophylaxis) in adults, AHA states that the usual dosage of IM penicillin G benzathine is 1.2 million units once every 4 weeks.375 The manufacturers recommend that IM penicillin G benzathine be given in a dosage of 1.2 million units once monthly or 600,000 units once every 2 weeks for such prophylaxis.2,3

AHA and AAP state that an IM penicillin G benzathine regimen that uses a 4-week dosing interval seems adequate and is recommended for most patients in the US, but a 3-week dosing interval may be warranted and is recommended when there is a particularly high risk of rheumatic fever (e.g., recurrent acute rheumatic fever despite adherence to a 4-week regimen).292,375 There is some evidence that serum penicillin concentrations may decline to subtherapeutic concentrations before the fourth week in some patients37,323,375 and there is limited evidence of an increased frequency of prophylactic failure with a 4-week interval compared with a 3-week interval in areas with a high risk of rheumatic fever.37,38

Prevention of recurrent rheumatic fever requires long-term, continuous prophylaxis.292,375 (See Table 1.)

Adverse Effects

Adverse effects reported with penicillin G benzathine are similar to those reported with other natural penicillins.2,3,4,5,10

Serious and occasionally fatal hypersensitivity reactions, including anaphylaxis, have been reported with penicillins.2,3,4,5,611,615,713,769 Rash (maculopapular), exfoliative dermatitis, urticaria, laryngeal edema, fever, eosinophilia, other serum sickness-like reactions (e.g., chills, fever, edema, arthralgia, prostration), and anaphylaxis (including shock and death) have been reported with penicillin G.2,3,4,5,611,615,713,769 Fever and eosinophilia may frequently be the only reaction observed.3,4,5

Inadvertent IV administration of penicillin G benzathine has been associated with cardiorespiratory arrest and death.2,4,5

Inadvertent intravascular administration (including inadvertent direct intra-arterial injection or injection immediately adjacent to arteries) of penicillin G benzathine or fixed combinations containing penicillin G benzathine and penicillin G procaine has resulted in severe neurovascular damage (e.g., transverse myelitis with permanent paralysis, gangrene requiring amputation of digits and more proximal portions of extremities, necrosis and sloughing at and surrounding the injection site).2,4,5 These severe effects have been reported following injections into the buttock, thigh, and deltoid areas.2,4,5 Other serious complications of suspected intravascular administration include immediate pallor, mottling, or cyanosis of the extremity (both distal and proximal to the injection site), followed by bleb formation or severe edema requiring anterior and/or posterior compartment fasciotomy in the lower extremity.2,4,5 These severe effects and complications have occurred most often in infants and small children.2,4,5

For additional 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 benzathine and fixed combinations of penicillin G benzathine and penicillin G procaine are contraindicated in patients hypersensitive to any penicillin.2,3,4,5 The fixed combinations also are contraindicated in patients hypersensitive to procaine.4,5

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.2,3,4,5

Prior to administration of penicillin G benzathine or a fixed combination of penicillin G benzathine and penicillin G procaine, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens.2,3,4,5 There is clinical and laboratory evidence of partial cross-allergenicity among penicillins and other β-lactam antibiotics, including cephalosporins and cephamycins.2,3,4,5,611,615,769,770,779

Hypersensitivity reactions to penicillins are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens.2,3,4,5 Penicillin G benzathine and fixed combinations of penicillin G benzathine and penicillin G procaine should be used with caution in individuals with a history of clinically important allergies and/or asthma.2,3,4,5

If a hypersensitivity reaction occurs, the drug should be discontinued immediately and appropriate therapy instituted as indicated (e.g., epinephrine, corticosteroids, maintenance of an adequate airway and oxygen).2,3,4,5

If use of a fixed combination containing penicillin G benzathine and penicillin G procaine is being considered in a patient with a history of procaine sensitivity, a test dose of procaine (0.1 mL of a 1-2% solution of procaine) should be administered intradermally prior to IM administration of full doses of the fixed combination.4,5 Development of erythema or a wheal, flare, or eruption at the intradermal test site indicates procaine sensitivity and the patient should not receive a preparation containing penicillin G procaine.4,5 If a hypersensitivity reaction to procaine occurs, it should be treated by usual methods; antihistamines may be beneficial and barbiturates may be indicated if seizures occur.4,5

Special precaution should be taken to avoid IV, intravascular, or intra-arterial administration or injection of penicillin G benzathine or fixed combinations containing the drug into or near major peripheral nerves or blood vessels since inadvertent intravascular or intra-arterial injection may produce severe and/or permanent neurovascular damage and inadvertent IV administration has been associated with cardiorespiratory arrest and death.2,4,5 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.2,4,5

Renal and hematologic systems should be evaluated periodically during prolonged therapy with a fixed combination containing penicillin G benzathine and penicillin G procaine, particularly if high dosage is used.4,5

For additional information on precautions associated with the use of penicillin G benzathine, see Cautions: Precautions and Contraindications, in the Natural Penicillins General Statement 8:12.16.04.

Pediatric Precautions

Penicillin G benzathine should be used with caution in neonates and organ system function should be evaluated frequently in such patients.3

Renal clearance of penicillin G may be delayed in neonates and young infants because of incompletely developed renal function.3,61

Geriatric Precautions

Clinical studies of penicillin G benzathine or penicillin G procaine did not include sufficient numbers of patients 65 years of age or older to determine whether geriatric patients respond differently than younger patients.2,4,5 Other clinical experience has not identified differences in responses between geriatric and younger patients.2,4,5

Penicillin G is substantially eliminated by the kidneys and the risk of adverse effects may be greater in those with impaired renal function.2,4,5 Because geriatric patients are more likely to have reduced renal function, dosage should be selected with caution, usually starting at the low end of the dosage range, and renal function monitoring may be useful.2,4,5

Pregnancy and Lactation

Pregnancy

Reproduction studies evaluating penicillin G in mice, rats, and rabbits have not revealed evidence of impaired fertility or harm to the fetus.2,3,4,5,25 Although experience with use of penicillins during pregnancy has not shown any evidence of adverse effects on the fetus, there are no adequate or controlled studies using penicillin G benzathine in pregnant women.2,3,4,5

Some clinicians state that IM penicillin G benzathine is considered low risk25 and safe for use during pregnancy.61 The drug is included in the US Centers for Disease Control and Prevention (CDC) recommendations for the treatment of syphilis during pregnancy.344

The manufacturers state that penicillin G benzathine and fixed combinations containing penicillin G benzathine and penicillin G procaine should be used during pregnancy only when clearly needed.2,3,4,5

Lactation

Penicillin G is distributed into milk.2,3,4,5,61,64,355,364,374 Some clinicians state that IM penicillin G benzathine usually is considered compatible with breast-feeding.25 The manufacturers and others state that penicillin G benzathine and fixed combinations of penicillin G benzathine and penicillin G procaine should be used with caution in nursing women.2,3,4,5,24

Spectrum

Based on its spectrum of activity, penicillin G benzathine is classified as a natural penicillin.10,61,64 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 Spectrumand 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 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.2,3,4,5,10,61,63,64 IM administration of penicillin G benzathine results in serum concentrations of penicillin G that are more prolonged, but lower, than those attained with an equivalent IM dose of penicillin G procaine or penicillin G potassium or sodium.2,3,10,61,64,70,81

Following IM administration of a single dose of penicillin G benzathine in adults,67,70,81 children,234 or neonates,353,365,371 peak serum concentrations of penicillin G are attained in 13-24 hours81,234,353,365,371 and usually are detectable for 1-4 weeks (depending on the dose).70,81,234,353,365,371

In adults, a single IM penicillin G benzathine dose of 1.2 million units results in serum penicillin G concentrations of 0.15, 0.03, and 0.003 units/mL at 1, 14, and 32 days, respectively, after the dose.64 In one study in adults who received IM penicillin G benzathine in a dosage of 2.4 million units administered once weekly for 3 successive weeks, serum penicillin G concentrations ranged from 0.04-0.48 units/mL at 7 days after the first dose, 0.06-0.48 units/mL at 7 days after the second dose, and 0.17-0.52 units/mL at 7 days after the third dose.324 In adults receiving IM penicillin G benzathine in a dosage of 1.2 million units once 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.323

Following a single IM dose of a fixed combination containing 1.2 million penicillin G units (i.e., 600,000 units as penicillin G benzathine and 600,000 units as penicillin G procaine; Bicillin^® C-R) in adults, peak blood penicillin G concentrations were 2.1-2.6 units/mL within 3 hours and blood concentrations averaged 0.75 units/mL at 12 hours, 0.28 units/mL at 24 hours, and 0.04 units/mL at 7 days.5

Following a single IM dose of a fixed combination containing 1.2 million penicillin G units (i.e., 900,000 units as penicillin G benzathine and 300,000 units as penicillin G procaine; Bicillin^® C-R 900/300) in patients weighing 45-64 kg, average blood penicillin G concentrations were 0.24 units/mL at 24 hours, 0.039 units/mL at 7 days, and 0.024 units/mL at 10 days after the dose.4

In a study in children 1.8-10.7 years of age who received a single IM penicillin G benzathine dose of 600,000 units if they weighed less than 27 kg or 1.2 million units if they weighed more than 27 kg, peak serum penicillin G concentrations occurred 24 hours after the dose and ranged from 0.11-0.2 mcg/mL.234 In these children, serum penicillin G concentrations ranged from 0.04-0.19 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.234 In children weighing 11.9-22.6 kg, IM administration of a single dose of a fixed combination containing 1.2 million penicillin G units (900,000 units as penicillin G benzathine and 300,000 units as penicillin G procaine) resulted in peak serum penicillin G concentrations that occurred 1 hour after the dose and averaged 3.9 mcg/mL.234 Serum penicillin G concentrations in these children 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.234

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.365 In another study in neonates, IM administration of a single penicillin G benzathine dose of 100,000 units resulted in serum penicillin G concentrations that ranged from 1.18-3.9 mcg/mL at 24 hours after the dose and were still detectable 5 days after the dose.353

Distribution

Following IM administration of penicillin G benzathine, penicillin G is widely distributed throughout the body in varying amounts.2,3,4,5 Highest concentrations generally are attained in the kidneys, with lower amounts in the liver, skin, and intestines.2,3,4,5

Minimal concentrations of penicillin G generally are attained in CSF following IM administration of penicillin G benzathine in patients with inflamed or uninflamed meninges.324,353,360 The minimum treponemicidal concentration of penicillin G is generally defined as 0.03 units/mL or 0.02 mcg/mL.325,354 In one study in adults who received IM penicillin G benzathine given in a dosage of 3.6 million units 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.360 In another study in adults who received IM penicillin G benzathine in a dosage of 2.4 or 4.8 million units administered 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.324 In a 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 0.012-0.2 mcg/mL; however, CSF penicillin G concentrations were less than 0.01 mcg/mL 48 hours after the dose.353

In a study in children who received a single IM dose of penicillin G benzathine of 600,000 units 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.330

Penicillin G is about 60% bound to serum proteins.2,3,4,5

Penicillin G crosses the placenta40,61 and is distributed into milk.2,3,4,5,61,64,355,364,374

Elimination

Following IM administration of penicillin G benzathine, the drug is slowly absorbed and hydrolyzed to penicillin G and elimination of penicillin G in urine continues over a prolonged period of time.64,234 Penicillin G and its metabolites are excreted in urine mainly by tubular secretion.2,3,4,5,64,320,348

Penicillin G has been detected in urine for up to 12 weeks after a single IM penicillin G benzathine dose of 1.2 million units.64 In a study in children 1.8-10.7 years of age who received a single IM dose of penicillin G benzathine of 600,000 units or 1.2 million units, urinary penicillin G concentrations 30 days after the dose ranged from 0.6-12.5 mcg/mL.234 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 at 12 days after the dose.365

The serum half-life of penicillin G may be prolonged in patients with impaired renal function.64,320,348

Renal clearance of penicillin G is delayed in neonates and young infants.2,3,4,5,64

Renal clearance of penicillin G may be increased in pregnant women40,61 during the second and third trimesters.40

Chemistry and Stability

Chemistry

Penicillin G benzathine is a natural penicillin.10,61 The drug is the benzathine tetrahydrate salt of penicillin G.64 Penicillin G benzathine is hydrolyzed in vivo to penicillin G2,3,61,72 and is frequently referred to as a long-acting, depot, or repository form of penicillin G.61

Penicillin G benzathine occurs as a white, crystalline powder.2,3 The drug is very slightly soluble in water2,3 and sparingly soluble in alcohol.2 Potency of penicillin G benzathine generally is expressed in terms of penicillin G units,2,3,4,5,10,292,344,375,580 but also has been expressed as mg of penicillin G.61

Commercially available penicillin G benzathine suspension for IM injection is a viscous, opaque suspension of the drug in sterile water for injection.2,3 The IM suspension has a pH of 5-7.53 and is buffered with sodium citrate.2,3 The suspension contains methylparaben and propylparaben as preservatives and also contains povidone, lecithin, and carboxymethylcellulose.2,3

Penicillin G benzathine also is commercially available in fixed combination with penicillin G procaine as a viscous, opaque, aqueous suspension for IM injection.4,5 Each 2 mL of fixed-combination suspension contains the equivalent of 1.2 million units of penicillin G in a formulation containing the equivalent of 600,000 units of penicillin G as the benzathine salt and 600,000 units of penicillin G as the procaine salt (Bicillin^® C-R)5 or a formulation containing the equivalent of 900,000 units of penicillin G as the benzathine salt and 300,000 units of penicillin G as the procaine salt (Bicillin^® C-R 900/300).4

Stability

Commercially available penicillin G benzathine suspension for IM injection should be stored at 2-8°C; freezing should be avoided.2,3

The fixed combinations of penicillin G benzathine and penicillin G procaine for IM injection should be stored at 2-8°C; freezing should be avoided.4,5

Additional Information

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.

2. Pfizer. Bicillin^® L-A (penicillin G benzathine) injectable suspension prescribing information. New York, NY; 2016 Jun.

3. Pfizer. Permapen^® Isoject^® (penicillin G benzathine) injectable suspension 1,200,000 units for intramuscular use only prescribing information. New York, NY; undated.

4. Pfizer. Bicillin^® C-R 900/300 (penicillin G benzathine and penicillin G procaine) injectable suspension for deep IM injection only prescribing information. New York, NY; 2016 Jun.

5. Pfizer. Bicillin^® C-R (penicillin G benzathine and penicillin G procaine) injectable suspension disposable syringe for deep IM injection only prescribing information. New York, NY; 2016 Jun.

8. Sandoz. Penicillin G sodium for injection, USP 5 million units prescribing information. Princeton, NJ; 2014 May.

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