Penicillin G is a natural penicillin antibiotic.
Uses
Penicillin G potassium or sodium is used parenterally when rapid and high concentrations of penicillin G are required, as in the treatment of septicemia, meningitis, pericarditis, endocarditis, severe pneumonia, or other serious infections caused by organisms susceptible to penicillin G.
For specific information on the uses of penicillin G potassium and penicillin G sodium, see Uses in the Natural Penicillins General Statement 8:12.16.04.
Dosage and Administration
Reconstitution and Administration
Penicillin G potassium is administered by IM injection or by continuous or intermittent IV infusion. The drug has also been administered orally and by intrapleural, intra-articular, and other local instillations. Penicillin G sodium is administered IM or by continuous IV infusion.
Oral dosage forms of penicillin G are no longer commercially available in the US.
Penicillin G potassium or sodium powders for injection should be reconstituted with the amount of diluent specified by the manufacturer. Depending on the route of administration, the powders for injection are generally reconstituted with sterile water for injection, 0.9% sodium chloride injection, or 5% dextrose injection.To reconstitute penicillin G potassium or sodium powder for injection, the powder should be loosened in the vial. Then, the vial should be held horizontally and rotated while slowly directing the stream of diluent against the wall of the vial; the vial should be shaken vigorously after the diluent has been added.
IM Administration
For IM administration, penicillin G potassium or sodium solutions containing up to 100,000 units/mL may be used with a minimum of discomfort; higher concentrations are physically possible and may be used when needed. Vials containing 10 or 20 million units of penicillin G potassium are intended for IV administration only and should not be given IM following reconstitution.
IV Administration
Penicillin G potassium or sodium should generally be given IV when large doses (10 million units or more) are required. For continuous IV infusion, reconstituted solutions of penicillin G potassium or sodium generally should be added to 1-2 L of a compatible IV solution.
The volume of IV fluid and rate of administration required by the patient in a 24-hour period should be determined and the appropriate daily dosage of penicillin G added to the fluid. For example, if an adult patient requires 2 L of fluid in 24 hours and a dosage of 10 million units of penicillin G daily, 5 million units can be added to 1 L of IV solution and the rate of administration adjusted so that the liter of fluid will be infused over 12 hours.
For intermittent IV infusion, penicillin G potassium or sodium should generally be infused over 1-2 hours. One suggested method for adults is to administer 1/6 or 1/4 of the total daily dose as a 1- to 2-hour infusion every 4 or 6 hours, respectively.
Divided doses of the drug have also been infused intermittently IV over 15-30 minutes in neonates and children. Thawed solutions of the commercially available frozen penicillin G potassium injection in dextrose should be administered by IV infusion. The commercially available frozen penicillin G potassium injections should not be thawed by warming them in a water bath or by exposure to microwave radiation.
A precipitate may form while the commercially available frozen injection in dextrose is frozen; however, this usually will dissolve with little or no agitation upon reaching room temperature, and the potency of penicillin G potassium frozen injection is not affected. After thawing at room temperature, the injections should be agitated and the container checked for minute leaks by firmly squeezing the bag.
The injection should be discarded if the container seal or outlet ports are not intact or leaks are found or if the solution is cloudy or contains a precipitate. Additives should not be introduced into the injection. The injection should not be used in series connections with other plastic containers, since such use could result in air embolism from residual air being drawn from the primary container before administration of fluid from the secondary container is complete.
Dosage
Dosage of penicillin G potassium and penicillin G sodium is expressed in terms of USP penicillin G units.
Adult Dosage
The minimum parenteral dosage of penicillin G potassium for the treatment of severe infections (e.g., bacteremia, pneumonia, pericarditis, empyema, meningitis) caused by susceptible streptococci or nonpenicillinase-producing staphylococci is 5 million units daily. Some clinicians suggest that adults with meningitis caused by susceptible organisms receive 15 million units daily given IV in divided doses every 4 hours.
Pediatric Dosage
Children 12 years of age or older generally may receive the usual adult dosage of penicillin G potassium or sodium.
Dosage of penicillin G potassium or sodium for children younger than 12 years of age should be based on the weight of the child and the severity of the infection. For neonates younger than 1 week of age, the American Academy of Pediatrics (AAP) recommends a dosage of 25,000-50,000 units every 12 hours in those who weigh 1.2-2 kg and a dosage of 25,000-50,000 units every 8 hours for those who weigh more than 2 kg.
For neonates 1-4 weeks of age, the AAP recommends a dosage of 25,000-50,000 units every 8 hours for those who weigh 1.2-2 kg and 25,000-50,000 units every 6 hours for those who weigh more than 2 kg. Neonates 4 weeks of age or younger who weigh less than 1.2 kg should receive 25,000-50,000 units of IM or IV penicillin G every 12 hours. The higher penicillin G dosage usually is recommended for the treatment of meningitis in neonates.
For the treatment of meningitis caused by group B streptococci, the AAP recommends that neonates 7 days of age or younger receive 250,000-450,000 units/kg daily IV in 3 divided doses and that neonates older than 7 days of age receive 450,000 units/kg daily given IV in 4 divided doses.
The AAP suggests that children older than 1 month of age receive an IM or IV dosage of penicillin G potassium or sodium of 25,000-50,000 units/kg daily given in 4 divided doses for the treatment of mild to moderate bacterial infections and an IM or IV dosage of 250,000-400,000 units/kg daily given in 4-6 divided doses for the treatment of severe bacterial infections. When penicillin G is used for the treatment of meningitis caused by susceptible strains of Streptococcus pneumoniae, the AAP recommends that pediatric patients 1 month of age or older receive a dosage of 250,000-400,000 units/kg daily given IV in 4-6 divided doses. A dosage of 250,000 units/kg daily given in 6 divided doses generally results in mean CSF concentrations of 0.8 mcg/mL sustained throughout the 4 hours between infusions.
Bacterial Endocarditis
For the treatment of enterococcal endocarditis, the American Heart Association (AHA) recommends that adults receive a penicillin G sodium dosage of 18-30 million units daily (by continuous IV infusion or in 6 equally divided IV doses) in conjunction with gentamicin (1 mg/kg IM or IV every 8 hours). Treatment with both drugs generally should be continued for 4-6 weeks, but patients who had symptoms of infection for more than 3 months before treatment was initiated and patients with prosthetic heart valves require a minimum of 6 weeks of therapy with both drugs.
For the treatment of endocarditis caused by penicillin-susceptible viridans streptococci or S. bovis (penicillin MIC 0.1 mcg/mL or less) in patients with native heart valves, the AHA recommends that adults receive a penicillin G sodium dosage of 12-18 million units daily (by continuous IV infusion or in 6 equally divided doses) for 4 weeks.
Alternatively, adults with uncomplicated endocarditis caused by these organisms who are at low risk for adverse effects related to aminoglycoside therapy may receive a 2-week regimen consisting of 12-18 million units of penicillin G daily (by continuous IV infusion or in 6 equally divided doses) given with gentamicin (1 mg/kg IM or IV every 8 hours). The 2-week regimen is not recommended for patients with complications such as extracardiac foci of infection or intracardiac abscesses.
Patients with endocarditis caused by viridans streptococci or S. bovis that involves prosthetic valves or other prosthetic materials should receive the treatment regimen recommended for enterococcal endocarditis or, alternatively, a 6-week regimen of penicillin G with gentamicin given concomitantly during the first 2 weeks. For adults with endocarditis caused by strains of viridans streptococci or S. bovis that are relatively resistant to penicillin G (penicillin MICs greater than 0.1 mcg/mL but less than 0.5 mcg/mL), the AHA recommends a penicillin G sodium dosage of 18 million units daily (by continuous IV infusion or in 6 equally divided IV doses) given for 4 weeks; gentamicin (1 mg/kg IM or IV every 8 hours) should be given concomitantly for the first 2 weeks.
Patients with endocarditis caused by strains of viridans streptococci that require higher concentrations of penicillin G for in vitro inhibition (i.e., penicillin MICs of 0.5 mcg/mL or greater) or endocarditis caused by nutritionally variant viridans streptococci should receive the treatment regimen recommended for enterococcal endocarditis.
Anthrax
For the treatment of anthrax caused by susceptible Bacillus anthracis that occurs as the result of naturally occurring or endemic anthrax exposure, the minimum parenteral dosage of penicillin G potassium or sodium is 5 million units daily given in divided doses; IV dosages up to 20 million units daily have been used in the treatment of anthrax septicemia and intestinal, pulmonary, and meningeal anthrax. Some clinicians recommend that adults receive IV penicillin G in a dosage of 8-12 million units daily given in divided doses every 4-6 hours and that children receive a dosage of 100,000-150,000 units/kg daily given in divided doses every 4-6 hours for the treatment of anthrax.
For the treatment of anthrax that occurs as the result of natural or endemic anthrax exposures, some clinicians recommend that penicillin G therapy should be continued for at least 14 days after symptoms abate.
For the treatment of inhalational anthrax that occurs as the result of exposure to B. anthracis spores in the context of biologic warfare or bioterrorism, the US Centers for Disease Control and Prevention (CDC) and the US Working Group on Civilian Biodefense recommend that treatment be initiated with a multiple-drug parenteral regimen that includes ciprofloxacin or doxycycline and 1 or 2 anti-infective agents predicted to be effective.
A multiple-drug parenteral regimen also is recommended for the initial treatment of cutaneous anthrax if there are signs of systemic involvement, extensive edema, or lesions on the head or neck. Because of concerns regarding possible penicillin resistance or induction of penicillin resistance during treatment, the CDC states that use of a penicillin alone is not recommended for the treatment of inhalational anthrax that occurs as the result of biologic warfare or bioterrorism when high concentrations of the organism are likely to be present, although penicillin can be included in appropriate combination regimens.
Some experts suggest that if IV penicillin G is used in the treatment of anthrax in the context of biologic warfare or bioterrorism when the organism has been shown to be susceptible to penicillin, adults can receive penicillin G in a dosage of 4 million units IV every 4 hours and children younger than 12 years of age may receive 50,000 units/kg IV every 6 hours.
Oral anti-infective therapy may be substituted for IV therapy as soon as the patient’s clinical condition improves. Because of the possible persistence of anthrax spores in lung tissue following an aerosol exposure in the context of biologic warfare or bioterrorism, the CDC and other experts recommend that anti-infective therapy should be continued for 60 days. 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 AAP recommends a dosage of penicillin G potassium or sodium of 100,000-150,000 units/kg daily given IV in 4 divided doses daily for 14 days.
If penicillin G potassium or sodium is used to eliminate the diphtheria carrier state in adults known to carry toxigenic strains of Corynebacterium diphtheriae, the usual dosage is 300,000-400,000 units daily given IM in divided doses for 10-12 days.
Listeria Infections
For the treatment of infections caused by L. monocytogenes, the usual parenteral dosage of penicillin G potassium or sodium for neonates is 500,000 to 1 million units daily. Adults with Listeria meningitis should receive 15-20 million units daily given IV for 2 weeks and adults with Listeria endocarditis should receive the same IV dosage daily for 4 weeks.
Infections Caused by Erysipelothrix rhusiopathiae
The usual adult parenteral dosage of penicillin G potassium or sodium for the treatment of Erysipelothrix endocarditis is 2-20 million units daily for 4-6 weeks.
Neisseria meningitidis Infections
The usual parenteral dosage of penicillin G potassium or sodium for the treatment of meningitis caused by susceptible N. meningitidis in adults is 1-2 million units given IM every 2 hours or 20-30 million units daily given by continuous IV infusion for at least 10-14 days.
Pasteurella multocida Infections
For the treatment of serious infections caused by Pasteurella multocida (e.g., bacteremia, meningitis) in adults, the usual parenteral dosage of penicillin G potassium or sodium is 4-6 million units daily for 2 weeks. Infections Caused by Enterobacteriaceae Although the manufacturers state that bacteremia caused by susceptible Enterobacteriaceae (e.g., Escherichia coli, Enterobacter aerogenes, Alcaligenes faecalis, Salmonella, Shigella, Proteus mirabilis) may be treated with a parenteral penicillin G potassium or sodium dosage of 20-80 million units daily, other more effective anti-infectives generally are used for the treatment of these infections (e.g., third generation cephalosporins, aminoglycosides, aminopenicillins, extended-spectrum penicillins).
Clostridium Infections
The manufacturers state that when penicillin G potassium or sodium is used in the treatment of Clostridium infections, the usual parenteral dosage in adults is 20 million units daily. When used in the management of wound botulism as an adjunct to botulinum antitoxin (available from the CDC), supportive care, and surgical debridement, IV penicillin G has been given in a dosage of 2 million units every 4 hours with IV metronidazole (250 mg every 6 hours). Anti-infectives have no known direct effects on botulinum toxin but may be indicated to eradicate C. botulinum at the wound site.
Actinomycosis
For the treatment of cervicofacial actinomycosis in adults, the usual parenteral dosage of penicillin G potassium or sodium is 1-6 million units daily. For the treatment of pulmonary or abdominal actinomycosis in adults, an IV dosage of 10-20 million units daily is used. Prolonged therapy with the drug (1.5-18 months or longer) may be necessary. Many clinicians recommend that patients with pulmonary actinomycosis or other severe infections caused by the organism receive 4-6 weeks of therapy with IV penicillin G potassium or sodium followed by 6-12 additional months of therapy with oral penicillin V or oral tetracycline hydrochloride.
Infections Caused by Fusobacterium
The usual parenteral dosage of penicillin G potassium or sodium for the treatment of severe forms of necrotizing ulcerative gingivitis or Fusobacterium infections of the lower respiratory tract and genital area in adults is 5-10 million units daily.
Syphilis Neurosyphilis
For the treatment of neurosyphilis, the CDC recommend that adults and adolescents receive 18-24 million units of IV penicillin G potassium or sodium daily (given as 3-4 million units every 4 hours or by continuous IV infusion) for 10-14 days; 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).
Congenital Syphilis
For the treatment of congenital syphilis, the CDC and AAP recommend that symptomatic neonates and neonates with proven or presumed congenital syphilis receive a penicillin G potassium or sodium dosage of 100,000-150,000 units/kg daily, administered as 50,000 units/kg IV every 12 hours during the first 7 days of life and every 8 hours thereafter for a total duration of 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.
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 IV penicillin G potassium or sodium in a dosage of 200,000-300,000 units/kg daily (given in 50,000 units/kg every 4-6 hours) for 10 days.
Some clinicians recommend that this regimen be followed by a regimen of IM penicillin G benzathine (50,000 units/kg once weekly for 1-3 weeks).
Lyme Disease
As an alternative to therapy with IV ceftriaxone or IV cefotaxime for the treatment of serious neurologic, cardiac, and/or arthritic manifestations of early or late Lyme disease, the AAP, Infectious Diseases Society of America (IDSA), and other clinicians recommend treatment with IV penicillin G for 14-28 days. For the treatment of patients with early Lyme disease who have acute neurologic disease manifested by meningitis or radiculopathy, adults should receive IV penicillin G 18-24 million units daily in 6 divided doses (every 4 hours) for 14-28 days as an alternative to treatment with IV ceftriaxone; children should receive 200,000-400,000 units/kg of IV penicillin G daily (maximum of 18-24 million units daily) in 4 or 6 divided doses (every 4 or 6 hours) for 14-28 days as an alternative to IV ceftriaxone or IV cefotaxime.
For patients with late Lyme disease and associated neurologic disease affecting the CNS or peripheral nervous system (e.g., neuropathy, encephalopathy) and documented by CSF analysis, adults should receive IV penicillin G 18-24 million units daily in 4 or 6 divided doses (every 4-6 hours) for 14-28 days as an alternative to treatment with IV ceftriaxone; children should receive 200,000-400,000 units/kg of IV penicillin G daily (maximum of 18-24 million units daily) in 4 or 6 divided doses (every 4-6 hours) for 14-28 days as an alternative to IV ceftriaxone or IV cefotaxime. Additional courses of antibiotic therapy generally are not recommended unless relapse of neurologic disease is documented with reliable objective measures.
For the treatment of severe Lyme carditis manifested by third-degree AV heart block or a PR-interval exceeding 0.3 seconds, adults should receive IV penicillin G 18-24 million units daily in 4 or 6 divided doses (every 4 or 6 hours) for 14-21 days and children should receive 200,000-400,000 units/kg of IV penicillin G daily (maximum of 18-24 million units daily) in 4 or 6 divided doses (every 4-6 hours) for 14-21 days.(For a more complete discussion of Lyme disease, see Lyme Disease under Uses: Spirochetal Infections, in the Tetracyclines General Statement 8:12.24.)
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 dosage of parenteral penicillin G potassium or sodium is 12-15 million units daily in adults for at least 3-4 weeks.
Prevention of Perinatal Group B Streptococcal Disease
When intrapartum chemoprophylaxis for the prevention of perinatal group B streptococcal (GBS) disease is indicated in the mother to prevent early-onset GBS disease in her neonate, the CDC and AAP recommend that a single dose of 5 million units of IV penicillin G be given at onset of labor or after membrane rupture followed by 2.5 million units IV every 4 hours until delivery. Regardless of whether chemoprophylaxis was administered to the mother, appropriate diagnostic evaluations and anti-infective therapy should be initiated in the mother and/or neonate if signs or symptoms of active infection develop. For information on when prevention of perinatal GBS disease is indicated, see Uses: Prevention of Perinatal Group B Streptococcal Disease, in the Natural Penicillins General Statement 8:12.16.04.
Dosage in Renal and Hepatic Impairment
In patients with impaired renal and/or hepatic function, doses and/or frequency of administration of penicillin G must be modified in response to the degree of impairment, severity of the infection, and susceptibility of the causative organism.
Some clinicians suggest that patients who are uremic but have a creatinine clearance greater than 10 mL/minute receive a full loading dose of IM or IV penicillin G potassium or sodium followed by one-half the usual dose every 4-5 hours and that patients with creatinine clearances less than 10 mL/minute receive a full loading dose followed by one-half the usual dose every 8-10 hours. Alternatively, some clinicians suggest that if the usual dosing interval for penicillin G potassium or sodium in patients with normal renal function (creatinine clearances greater than 50 mL/minute) is every 6 or 8 hours, then the usual dose should be given at 8- to 12-hour intervals or 12- to 18-hour intervals in patients with creatinine clearances of 10-50 or less than 10 mL/minute, respectively.
Some clinicians suggest that a maximum dosage of 4-10 million units of penicillin G potassium or sodium daily be used in adults with severe renal failure. In patients with impaired hepatic function in addition to impaired renal function, further dosage reductions may be advisable.
Cautions
Adverse Effects
Adverse effects reported with penicillin G potassium and penicillin G sodium are similar to those reported with other natural penicillins. For information on adverse effects reported with penicillin G, see Cautions in the Natural Penicillins General Statement 8:12.16.04.
Precautions and Contraindications
Penicillin G potassium and penicillin G sodium share 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 potassium or sodium, 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 potassium and penicillin G sodium are contraindicated in patients who are hypersensitive to any penicillin.
Renal and hematologic systems should be evaluated periodically during prolonged therapy with parenteral penicillin G potassium or sodium, particularly if high dosage is used. In such situations, use of penicillin G for longer than 2 weeks may be associated with an increased risk of neutropenia and an increased incidence of serum sickness-like reactions. The possibility of electrolyte imbalance should be considered when high doses (greater than 10 million units) of penicillin G potassium or sodium are administered IV. If high doses of the drugs are given IV, the drugs should be administered slowly and electrolyte balance and renal and hematologic systems should be evaluated frequently.
The patient’s renal, cardiac, and vascular status should be evaluated and if impairment of function is suspected or known to exist, a reduction in dosage should be considered. For a more complete discussion of these and other precautions associated with the use of penicillin G potassium or sodium, see Cautions: Precautions and Contraindications, in the Natural Penicillins General Statement 8:12.16.04.
Pregnancy and Lactation
Safe use of penicillin G potassium or sodium during pregnancy has not been definitely established. There are no adequate or controlled studies using penicillin G in pregnant women, and the drug should be used during pregnancy only when clearly needed. Use of penicillin G potassium or sodium 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 potassium or sodium should be used with caution in nursing women.
Spectrum
Based on its spectrum of activity, penicillin G 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 8:12.16.04 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
Penicillin G potassium is very susceptible to acid-catalyzed hydrolysis and only about 15-30% of an orally administered dose of the drug is absorbed in healthy, fasting adults. Following oral administration (oral dosage forms of penicillin G potassium are no longer commercially available in the US) of a single dose of 400,000 units of penicillin G potassium in healthy, fasting adults, peak penicillin G serum concentrations are generally attained within 30-60 minutes and average approximately 0.5 units/mL.
Presence of food in the GI tract generally decreases the rate and extent of oral absorption of penicillin G potassium. Penicillin G potassium and penicillin G sodium are rapidly absorbed followed IM administration, and serum concentrations of penicillin G are generally the same following IM administration of equivalent doses of either salt.
Following IM administration in adults of a single penicillin G potassium or sodium dose of 600,000 or 1 million units, peak serum concentrations of penicillin G are generally attained within 15-30 minutes and average 6-8 and 20 units/mL, respectively. In one study in neonates 6 days of age or younger who received penicillin G potassium IM in a dosage of 25,000 units/kg every 12 hours, serum penicillin G concentrations ranged from 12.5-36, 7.8-35.1,4.4-35.1, 0.7-21.9, and 0.3-9.2 mcg/mL at 30 minutes, 1 hour, 2 hours, 4 hours, and 12 hours, respectively, after a dose.
Following intermittent IV infusion of 2 million units of penicillin G potassium or sodium every 2 hours or 3 million units every 3 hours, serum penicillin G concentrations reportedly average 20 mcg/mL. Penicillin G potassium or sodium is absorbed from the peritoneal cavity following local instillation and is also absorbed from pleural surfaces, pericardium, and joint cavities. Penicillin G is not absorbed through unbroken skin.
Distribution
Penicillin G is widely distributed following absorption from the GI tract (oral dosage forms of penicillin G potassium are no longer commercially available in the US) or injection sites. The volume of distribution of penicillin G is reportedly 0.53-0.67 L/kg in adults with normal renal function.
Minimal concentrations of penicillin G are generally attained in CSF following administration of penicillin G potassium or sodium in patients with uninflamed meninges; however, higher penicillin G concentrations are attained in CSF when the meninges are inflamed or when oral probenecid is administered concomitantly.
Following IV administration of penicillin G sodium, concentrations of penicillin G in CSF reportedly range from 0-10% of concurrent serum concentrations of the drug in patients with normal meninges. In 2 adults with syphilis who received a daily IV dosage of 5 or 10 million units of penicillin G potassium for at least 10 days, penicillin G concentrations in CSF immediately following completion of therapy were 0.3 and 2.4 mcg/mL, respectively.
In one study in children 2 weeks to 11 years of age with meningitis who received penicillin G potassium in a daily dosage of 250,000 units/kg given in 6 divided doses by IV infusion over 15 minutes, penicillin G concentrations in CSF specimens obtained between doses averaged 0.8, 0.7, and 0.3 mcg/mL on the first, fifth, and tenth days of therapy, respectively. Penicillin G is approximately 45-68% bound to serum proteins. Penicillin G readily crosses the placenta, although cord blood concentrations of the drug may be less than maternal serum concentrations. Penicillin G is distributed into milk.
Elimination
The serum half-life of penicillin G in adults with normal renal function is reportedly 0.4-0.9 hours. Approximately 16-30% of an IM dose of penicillin G sodium is metabolized to penicilloic acid which is microbiologically inactive.
Small amounts of 6-aminopenicillanic acid (6-APA) have also been found in the urine of patients receiving penicillin G. In addition, the drug appears to be hydroxylated to a small extent to one or more microbiologically active metabolites which are also excreted in urine.
Penicillin G and its metabolites are excreted in urine mainly by tubular secretion. Small amounts of the drug are also excreted in bile. Following IM or IV administration of a single dose of penicillin G sodium in adults with normal renal function, 60% or more of the dose is excreted in urine as unchanged drug and active metabolites within 6 hours. Approximately 20% of an oral dose (oral dosage forms of penicillin G potassium are no longer commercially available in the US) of penicillin G potassium is excreted in urine in patients with normal renal function.
Serum concentrations of penicillin G may be higher and the serum half-life prolonged in patients with impaired renal function. The serum half-life of the drug is reportedly 1-2 hours in azotemic patients with serum creatinine concentrations less than 3 mg/dL and ranges from 6-20 hours in anuric patients. In anuric patients with hepatic impairment, the serum half-life of penicillin G may be 2-3 times more prolonged than in anuric patients with normal hepatic function.
The serum half-life of penicillin G in neonates varies inversely with age and appears to be independent of birthweight. The serum half-life of the drug is reportedly 3.2-3. hours in neonates 6 days of age or younger, 1.2-2. hours in neonates 7-13 days of age, and 0.9-1.9 hours in neonates 14 days of age or older. Penicillin G is removed by hemodialysis, but is only minimally removed by peritoneal dialysis.
Chemistry and Stability
Chemistry
Penicillin G is a natural penicillin produced by fermentation of Penicillium chrysogenum in a medium containing phenylacetic acid. Penicillin G potassium and penicillin G sodium are frequently referred to as aqueous, crystalline forms of penicillin G.
Penicillin G potassium occurs as colorless or white crystals or a white, crystalline powder. Penicillin G sodium occurs as colorless or white crystals or a white to slightly yellow, crystalline powder. The drugs are odorless or practically odorless.
Penicillin G potassium is very soluble in water, in 0.9% sodium chloride, and in dextrose solutions and is sparingly soluble in alcohol. Penicillin G sodium has an approximate solubility of 25 mg/mL in water at 25°C. Penicillin G has a pKa of 2.76. Potency of penicillin G potassium and penicillin G sodium is generally expressed in terms of USP penicillin G units rather than weight.
Each mg of penicillin G potassium has a potency of 1440-1680 USP penicillin G units and contains 80.8-94.3% penicillin G. Each mg of penicillin G potassium powder for injection has a potency of 1355-1595 USP penicillin G units and contains 76.3-89.8% penicillin G and 4-5% sodium citrate of which not more than 0.15% may be citric acid. Each mg of penicillin G sodium has a potency of 1500-1750 USP penicillin G units and contains 84.5-98.5% penicillin G. Each mg of penicillin G sodium powder for injection has a potency of 1420-1667 USP penicillin G units and contains 80-93.% penicillin G and 4-5% sodium citrate of which not more than 0.15% may be citric acid.
Commercially available penicillin G potassium and penicillin G sodium powders for injection contain sodium citrate and citric acid as a buffer. Penicillin G potassium powder for injection contains 1.7 mEq of potassium and 0.3 mEq of sodium in each 1 million units of penicillin G. Penicillin G sodium powder for injection contains 2 mEq of sodium in each 1 million units of penicillin G.
Reconstituted solutions of penicillin G potassium or penicillin G sodium powders for injection containing 60 mg of penicillin G per mL have a pH of 6-8.5 or 6-7.5, respectively. The commercially available frozen penicillin G potassium in dextrose injections are sterile, iso-osmotic, nonpyrogenic solutions of the drug; about 2, 1.15, or 0.35 g of dextrose has been added to the 1-, 2-, or 3-million unit injections of penicillin G potassium, respectively, to adjust osmolality to about 300 mOsm/kg. Penicillin G potassium in dextrose frozen injections also contain hydrochloric acid and/or sodium hydroxide to adjust pH to 5.5-8 and sodium citrate as a buffer.
Stability
Penicillin G potassium and penicillin G sodium are moderately hygroscopic and dry powders of the drugs should be protected from moisture to prevent hydrolysis. Solutions of the drugs retain substantially full potency for several days when stored at a temperature less than 15°C, but are rapidly inactivated in the presence of acids, alkali hydroxides, glycerin, or oxidizing agents.
Commercially available penicillin G potassium or penicillin G sodium powders for injection may be stored at room temperature. Following reconstitution of the powders for injection, penicillin G potassium or penicillin G sodium solutions are stable for 7 days at 2-8°C. Solutions of the drugs prepared for IV administration are generally stable for 24 hours at room temperature.
The manufacturer states that the stability of the commercially available frozen penicillin G potassium injection may vary. These injections are stable for at least 90 days from the date of shipment when stored at -20°C. The frozen injection should be thawed at room temperature (25°C) or under refrigeration (5°C) and, once thawed, should not be refrozen. Thawed solutions of the commercially available frozen injection are stable for 24 hours at room temperature (25°C) or 14 days when refrigerated at 5°C.
The commercially available frozen injection of the drug is provided in a plastic container fabricated from specially formulated plastic PL 2040 (Galaxy®). Solutions in contact with the plastic can leach out some of its chemical components in very small amounts within the expiration period of the injection; however, safety of the plastic has been confirmed in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies.
Small amounts of polymer conjugation products reportedly form in solutions of penicillin G during in vitro storage, especially when high concentrations of the drug are stored at room temperature.
Because these polymers may play a role in hypersensitivity reactions to the drug, some clinicians recommend that, although potency may not be adversely affected, reconstituted solutions of penicillin G potassium or penicillin G sodium should be refrigerated or used shortly following reconstitution. Penicillin G is potentially physically and/or chemically incompatible with some drugs, including aminoglycosides and tetracyclines, but the compatibility depends on several factors (e.g., concentrations of the drugs, specific diluents used, resulting pH, temperature).
For information on the in vitro and in vivo incompatibility of penicillins and aminoglycosides, see Drug Interactions: Aminoglycosides, in the Natural Penicillins General Statement 8:12..04.
Specialized references should be consulted for specific compatibility 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 potassium or sodium, see the Natural Penicillins General Statement 8:12..04.
Preparations
Penicillin G Potassium Parenteral For injection 5 million units (of Pfizerpen®, penicillin G) Pfizer 20 million units (of Pfizerpen®, penicillin G) Pfizer Penicillin G Potassium in Dextrose Parenteral Injection (frozen) 20,000 units (of penicillin Penicillin G Potassium in Iso- , for IV infusion G) per mL (1 million units) osmotic Dextrose Injection in 4% Dextrose Galaxy®, Baxter 40,000 units (of penicillin Penicillin G Potassium in Iso- G) per mL (2 million units) osmotic Dextrose Injection in 2.3% Dextrose Galaxy®, Baxter 60,000 units (of penicillin Penicillin G Potassium in 5% G) per mL (3 million units) Dextrose Injection Galaxy®, in 0.7% Dextrose Baxter Penicillin G Sodium Parenteral For injection 5 million units (of Penicillin G Sodium for penicillin G) Injection, Sandoz