PENICILLIN G POTASSIUM

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-Penicillin G potassium or sodium salts may be administered intravenously or intramuscularly. Outside of electrolyte content, there is no difference therapeutically between the sodium and potassium salts of penicillin G.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
Vials and pharmacy bulk package reconstitution:
-Reconstitute according to manufacturer's directions with a compatible IV infusion fluid, such as D5W or NS.
-For neonates, a dilution 25,000 units/ml has been recommended.
-Storage: After injection solution is mixed, the constituted solution may be stored in a refrigerator between 2 and 8 degrees C (36 and 46 degrees F) for a duration as specified by the manufacturer; do not freeze.

Frozen bag preparation:
-Thaw at room temperature. Do not force thaw. No reconstitution necessary.
-Storage: Prepared infusion solutions may be kept at room temperature for 24 hours or under refrigeration for 14 days.
-Do not refreeze thawed antibiotics.

Infusion:
-Intermittent IV infusions have been administered over 15-30 minutes for infants and children and over 1-2 hours for adults.

-For continuous infusion, determine the patient's daily fluid volume requirement and add the reconstituted solution to a compatible IV solution with half the daily dose administered over 12 hours.

Intramuscular Administration
NOTE: In general, IM administration of drugs in very low birth weight premature neonates is not practical due to small muscle mass, and absorption is unreliable due to hemodynamic instability that is relatively common in this population.
-Vials containing more than 5 Million Units are not intended for IM use. Dilute with a minimum amount of compatible diluent. Concentrations of 100,000 units/mL may be used IM with a minimum of discomfort. Higher concentrations may be administered when clinically necessary; however, when large doses are necessary, consider IV administration.
-Injection into the midlateral muscles of the thigh is preferred. In infants and small children, the periphery of the upper outer quadrant of the gluteus maximus should be used only if necessary (e.g., in burn patients) in order to avoid injury to the sciatic nerve.

Other Injectable Administration
Intrapleural or other local infusion
-If fluid is aspirated, give infusion volume equal to 1/4 or 1/2 the amount of fluid aspirated, otherwise, solution containing up to 100,000 units/ml may be used.

Hypersensitivity and dermatologic reactions are among the most frequent adverse reactions to the penicillins. Penicillin allergy has been reported in up to 20% of patients in the general population; however, around 90% of reported allergies are incorrectly reported and patients lack penicillin-specific IgE antibodies. The actual prevalence of penicillin allergy is likely no greater than 5%. These effects range from a benign rash to anaphylactoid reactions. Severe reactions such as anaphylaxis and anaphylactic shock occur rarely and may include angioedema, laryngeal edema, laryngospasm, bronchospasm, vascular collapse, and death. Other reactions that have been reported include rash (unspecified), maculopapular rash, urticaria, pruritus, serum sickness-like symptoms (fever, malaise, myalgia, arthralgia), contact dermatitis, and exfoliative dermatitis. Rash may develop after the first week and may cover the entire body, including the soles, palms, and oral mucosa. The rash usually disappears in 3-7 days. Other reactions which occur infrequently, but can be serious, include Stevens-Johnson syndrome and toxic epidermal necrolysis. Interstitial nephritis, a hypersensitivity reaction, with renal tubular necrosis (damage) been reported. Discontinuation of penicillin G usually resolves the interstitial nephritis.

Penicillin antibiotics have been associated with acute generalized exanthematous pustulosis (AGEP). The nonfollicular, pustular, erythematous rash starts suddenly, is associated with fever above 38 degrees C, and is distinct from pustular psoriasis, although biopsy results in each reveal spongiform subcorneal pustules. Drugs are the main cause of AGEP. A period of 2-3 weeks after an inciting drug exposure appears necessary for a first episode of AGEP. Unintentional reexposure may cause a second episode within 2 days. Clinical presentation is diverse with cutaneous lesions beyond erythema and pustules present in half of the cases. For example, bullous lesions, edema, purpura, pruritus, and mucosal erosions are possible. The mean duration of the pustules is 9.7 days followed by an annular desquamation, as long as the causative drug or factor is discontinued. The physiopathological mechanisms of AGEP have not been determined but the pathological criteria of edema, leukocytoclastic vasculitis, eosinophil exocytosis, and keratinocyte focal necrosis are distinctive. Pustule confluence or very small pustules may lead a clinician to make an incorrect diagnosis of TEN, of drug-induced erythroderma, or of staphylococcal scalded skin syndrome.

Phlebitis, injection site reaction (pain at injection site), and thrombophlebitis can occur with intravenous administration of penicillin G.

Gastrointestinal adverse events may occur in 2% to 5% of patients in the general population receiving penicillins. Nausea, vomiting, diarrhea, stomatitis, black or hairy tongue (tongue discoloration), and other symptoms of gastrointestinal irritation have been reported.

Microbial overgrowth and superinfection can occur with antibiotic use. C. difficile-associated diarrhea (CDAD) or pseudomembranous colitis has been reported with penicillin G. If pseudomembranous colitis is suspected or confirmed, ongoing antibacterial therapy not directed against C. difficile may need to be discontinued. Institute appropriate fluid and electrolyte management, protein supplementation, C. difficile-directed antibacterial therapy, and surgical evaluation as clinically appropriate.

Large doses (e.g., more than 10 million units/day) of penicillin G sodium IV can aggravate congestive heart failure due to the sodium content of the drug. Patients should be monitored for hypernatremia, fluid retention, or edema. Each million units of penicillin G sodium contains 2 mEq of sodium.

High-dose penicillin G therapy has been associated with seizures, hyperreflexia, myoclonic twitches (myoclonia), and coma. The risk of seizures appears to be higher in neonates, patients with renal impairment, and in patients who receive rapid IV administration. In animal studies of anticonvulsant efficacy, penicillin is sometimes used as the invoking agent. Large doses of penicillin G potassium IV can cause hyperkalemia, which can manifest as hyperreflexia, convulsion, and coma. Each million units of penicillin G potassium contains roughly 1.7 mEq of potassium.

Hematologic side effects associated with penicillin G therapy may include neutropenia which resolves after drug discontinuation. Combs-positive hemolytic anemia has been reported uncommonly and has occurred in adult patients treated with more than 10 million units/day and who have previously received large doses of penicillin. With large doses, bleeding can occur secondary to platelet dysfunction.

The Jarisch-Herxheimer reaction is a self-limiting systemic reaction that has been reported in the setting of spirochete infections, such as Lyme disease, syphilis, relapsing fever, and leptospirosis, after the initiation of antimicrobial therapy. It is characterized by fever, chills, myalgias, headache, exacerbation of cutaneous lesions, tachycardia, hyperventilation, vasodilation with flushing, and mild hypotension. Less commonly, symptoms may include meningitis, pulmonary failure, hepatic and renal dysfunction, myocardial injury, premature uterine contractions in pregnant patients, and worsening cerebral function as well as strokes and seizures. The reaction has been noted in up to 30% of patients with early Lyme disease. The timing of the reaction varies by underlying infection but typically presents within a few hours after the initiation of antibiotics. For Lyme disease, the reaction usually begins within 1 to 2 hours after starting therapy and disappears within 12 to 24 hours. The reaction after treatment in syphilis usually starts at 4 hours, peaks at 8 hours, and subsides by 16 hours whereas it starts at about 1 to 2 hours, peaks at 4 hours, and subsides by 8 hours after treatment in relapsing fever. The pathogenesis of this reaction is unknown but may be due to the release of spirochetal heat-stable pyrogen. Fluids and antipyretics can be used to alleviate symptoms and duration of the reaction if severe.

A false-positive reaction for glucose in the urine has been observed in patients receiving penicillins and using Benedict's solution, Fehling's solution, or Clinitest tablets for urine glucose testing. However, this reaction has not been observed with Tes-tape (glucose Enzymatic Test Strip, USP, Lilly) or Clinistix. Patients with diabetes who test their urine for glucose should use glucose tests based on enzymatic glucose oxidase reactions while on penicillin treatment.

Penicillin is contraindicated for use in patients with penicillin hypersensitivity. It should be used cautiously in patients with cephalosporin hypersensitivity or carbapenem hypersensitivity. These patients are more susceptible to cross-hypersensitivity reactions. Penicillin can cause a variety of hypersensitivity reactions ranging from mild rash to fatal anaphylaxis. Patients with allergies or allergic conditions including asthma may have a greater risk for hypersensitivity reactions to penicillins.

Penicillin G is eliminated primarily unchanged via renal tubular secretion. With normal renal function the drug is rapidly eliminated. In individuals with renal impairment or renal failure, excretion is considerably delayed. Incomplete development of renal function in neonates and infants may delay elimination of penicillin. Dosages of penicillin G may need to be reduced in these patients. Large doses of penicillin administered to patients with renal impairment have been associated with seizures.

Use large doses of parenteral penicillin G potassium or penicillin G sodium with caution in patients with electrolyte imbalance and those who are particularly sensitive to sodium intake (e.g., newborns, patients with heart failure or hypertension). Large doses of sodium or potassium may be administered daily as a result of the administration of these penicillin G salts and the amount of sodium and/or potassium can vary among products.

Consider pseudomembranous colitis in patients presenting with diarrhea after antibacterial use. Careful medical history is necessary as pseudomembranous colitis has been reported to occur over 2 months after the administration of antibacterial agents. Almost all antibacterial agents, such as penicillin G, have been associated with pseudomembranous colitis or C. difficile-associated diarrhea (CDAD) which may range in severity from mild to life-threatening. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

Description: Penicillin G (benzylpenicillin) is a naturally derived antibiotic for parenteral use. It is derived from Penicillium chrysogenum and is commercially available as salts of potassium, sodium, benzathine, and procaine. The potassium and sodium salts are referred to as the aqueous and crystalline forms of the drug and are administered intravenously or intramuscularly. Aqueous penicillin G is the drug of choice for group B Streptococcus (GBS) prophylaxis, neurosyphilis, and congenital syphilis. It is also used in treating GBS meningitis and endocarditis due to susceptible organisms. Overall electrolyte intake and needs should be assessed when choosing which salt format to administer. Aqueous penicillin G is FDA approved in pediatric patients as young as neonates.

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: Actinomyces bovis, Actinomyces israelii, Actinomyces sp., Alcaligenes faecalis, Bacillus anthracis, Clostridium sp., Corynebacterium diphtheriae, Erysipelothrix rhusiopathiae, Escherichia coli, Fusobacterium sp., Klebsiella aerogenes, Leptospira sp., Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella multocida, Proteus mirabilis, Salmonella sp., Shigella sp., Spirillum minus, Staphylococcus sp., Streptobacillus moniliformis, Streptococcus agalactiae (group B streptococci), Streptococcus dysgalactiae, Streptococcus pneumoniae, Streptococcus pyogenes (group A beta-hemolytic streptococci), Streptococcus sp., Streptococcus sp. (Group C), Streptococcus sp. (Group G), Streptococcus sp. (Group H), Streptococcus sp. (Group L), Streptococcus sp. (Group M), Treponema pallidum
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

This drug may also have activity against the following microorganisms: Borrelia burgdorferi, Haemophilus sp., Peptostreptococcus sp., Prevotella melaninogenica, Streptococcus bovis, Treponema carateum, Treponema endemicum, Treponema pertenue, Viridans streptococci
NOTE: Some organisms may not have been adequately studied during clinical trials; therefore, exclusion from this list does not necessarily negate the drug's activity against the organism.

For the treatment of pneumonia, including community-acquired pneumonia (CAP):
-for the general treatment of pneumonia:
Intravenous or Intramuscular dosage:
Neonates 0 to 7 days: 50,000 units/kg/dose IV or IM every 12 hours.
Neonates older than 7 days: 50,000 units/kg/dose IV or IM every 8 hours.
Infants, Children, and Adolescents: 150,000 to 300,000 units/kg/day (Max: 24 million units/day) IV or IM divided every 4 to 6 hours.
-for the empiric treatment of community-acquired pneumonia (CAP):
Intravenous or Intramuscular dosage:
Infants, Children, and Adolescents: 100,000 to 250,000 units/kg/day IV or IM divided every 4 to 6 hours for 5 to 7 days.
-for the treatment of CAP in pediatric patients due to S. pneumoniae (penicillin MIC 2 mcg/mL or less):
Intravenous or Intramuscular dosage:
Infants, Children, and Adolescents: 200,000 to 250,000 units/kg/day IV or IM divided every 4 to 6 hours for 5 to 7 days.
-for the treatment of CAP in pediatric patients due to Group A Streptococcus:
Intravenous or Intramuscular dosage:
Infants, Children, and Adolescents: 100,000 to 250,000 units/kg/day IV or IM divided every 4 to 6 hours for 5 to 7 days.

For the treatment of clostridial diseases*, including botulism*, gas gangrene*, and tetanus*:
-for the treatment of botulism* as adjunctive therapy to antitoxin:
Intravenous or Intramuscular dosage:
Neonates 0 to 7 days: 50,000 units/kg/dose IV or IM every 12 hours.
Neonates older than 7 days: 50,000 units/kg/dose IV or IM every 8 hours.
Infants, Children, and Adolescents: 100,000 to 300,000 units/kg/day (Max: 24 million units/day) IV or IM in divided doses every 4 to 6 hours.
-for the treatment of gas gangrene:
Intravenous or Intramuscular dosage:
Neonates 0 to 7 days: 50,000 units/kg/dose IV or IM every 12 hours. Penicillin plus clindamycin is recommended for necrotizing clostridial infections.
Neonates older than 7 days: 50,000 units/kg/dose IV or IM every 8 hours. Penicillin plus clindamycin is recommended for necrotizing clostridial infections.
Infants, Children, and Adolescents: 60,000 to 100,000 units/kg/dose IV every 6 hours. Penicillin plus clindamycin is recommended for necrotizing clostridial infections.
-for the treatment of tetanus*:
Intravenous or Intramuscular dosage:
Neonates 0 to 7 days: 50,000 units/kg/dose IV or IM every 12 hours.
Neonates older than 7 days: 50,000 units/kg/dose IV or IM every 8 hours.
Infants, Children, and Adolescents: 100,000 units/kg/day (Max: 12 million units/day) IV or IM in divided doses every 4 to 6 hours for 7 to 10 days.

For the treatment of anthrax*:
-for the treatment of systemic anthrax without aerosol exposure, including those with signs and symptoms of meningitis, as part of combination therapy*:
Intravenous or Intramuscular dosage:
Neonates 32 to 33 weeks gestation and 0 to 6 days: 100,000 units/kg/dose IV or IM every 12 hours for at least 14 days; may consider step-down to oral therapy.
Neonates 32 to 33 weeks gestation and 7 days and older: 100,000 units/kg/dose IV or IM every 8 hours for at least 14 days; may consider step-down to oral therapy.
Neonates 34 weeks gestation and older and 0 to 6 days: 100,000 units/kg/dose IV or IM every 8 hours for at least 14 days; may consider step-down to oral therapy.
Neonates 34 weeks gestation and older and 7 days and older: 100,000 units/kg/dose IV or IM every 6 hours for at least 14 days; may consider step-down to oral therapy.
Infants, Children, and Adolescents: 67,000 units/kg/dose (Max: 4 million units/dose) IV every 4 hours for at least 14 days; may consider step-down to oral therapy.
-for the treatment of systemic anthrax with aerosol exposure, including those with signs and symptoms of meningitis, as part of combination therapy*:
Intravenous or Intramuscular dosage:
Neonates 32 to 33 weeks gestation and 0 to 6 days: 100,000 units/kg/dose IV or IM every 12 hours for at least 14 days; may consider step-down to oral therapy. Transition to a postexposure prophylaxis regimen to complete a 60-day total treatment course from illness onset.
Neonates 32 to 33 weeks gestation and 7 days and older: 100,000 units/kg/dose IV or IM every 8 hours for at least 14 days; may consider step-down to oral therapy. Transition to a postexposure prophylaxis regimen to complete a 60-day total treatment course from illness onset.
Neonates 34 weeks gestation and older and 0 to 6 days: 100,000 units/kg/dose IV or IM every 8 hours for at least 14 days; may consider step-down to oral therapy. Transition to a postexposure prophylaxis regimen to complete a 60-day total treatment course from illness onset.
Neonates 34 weeks gestation and older and 7 days and older: 100,000 units/kg/dose IV or IM every 6 hours for at least 14 days; may consider step-down to oral therapy. Transition to a postexposure prophylaxis regimen to complete a 60-day total treatment course from illness onset.
Infants, Children, and Adolescents: 67,000 units/kg/dose (Max: 4 million units/dose) IV every 4 hours for at least 14 days; may consider step-down to oral therapy.
Immunocompromised Infants, Children, and Adolescents: 67,000 units/kg/dose (Max: 4 million units/dose) IV every 4 hours for at least 14 days; may consider step-down to oral therapy. Transition to a postexposure prophylaxis regimen to complete a 60-day total treatment course from illness onset.

For the treatment of infective endocarditis:
NOTE: For gonococcal endocarditis, see gonococcal infections.
-for the treatment of native valve endocarditis due to highly susceptible streptococci:
Intravenous or Intramuscular dosage:
Neonates 0 to 7 days*: 50,000 units/kg/dose IV or IM every 12 hours for 4 weeks.
Neonates older than 7 days*: 50,000 units/kg/dose IV or IM every 8 hours for 4 weeks.
Infants, Children, and Adolescents: 200,000 to 300,000 units/kg/day (Max: 24 million units/day) IV or IM divided every 4 hours for 4 weeks. Optimal therapy is not established for S. pneumoniae. The FDA-approved dose is 150,000 to 300,000 units/kg/day IV or IM divided every 4 to 6 hours.
-for the treatment of native valve endocarditis due to relatively resistant streptococci:
Intravenous or Intramuscular dosage:
Neonates 0 to 7 days*: 50,000 units/kg/dose IV or IM every 12 hours for 4 weeks plus gentamicin for 2 weeks.
Neonates older than 7 days*: 50,000 units/kg/dose IV or IM every 8 hours for 4 weeks plus gentamicin for 2 weeks.
Infants, Children, and Adolescents: 200,000 to 300,000 units/kg/day (Max: 24 million units/day) IV or IM divided every 4 hours for 4 weeks plus gentamicin for 2 weeks. Penicillin G is not recommended for penicillin-resistant S. pneumoniae. The FDA-approved dose is 150,000 to 300,000 units/kg/day IV or IM divided every 4 to 6 hours.
-for the treatment of prosthetic valve endocarditis due to highly susceptible streptococci:
Intravenous or Intramuscular dosage:
Neonates 0 to 7 days*: 50,000 units/kg/dose IV or IM every 12 hours for 6 weeks plus gentamicin for 2 weeks.
Neonates older than 7 days*: 50,000 units/kg/dose IV or IM every 8 hours for 6 weeks plus gentamicin for 2 weeks.
Infants, Children, and Adolescents: 200,000 to 300,000 units/kg/day (Max: 24 million units/day) IV or IM divided every 4 hours for 6 weeks plus gentamicin for 2 weeks. The FDA-approved dose is 150,000 to 300,000 units/kg/day IV or IM divided every 4 to 6 hours.
-for the treatment of prosthetic valve endocarditis due to relatively resistant streptococci:
Intravenous or Intramuscular dosage:
Neonates 0 to 7 days*: 50,000 units/kg/dose IV or IM every 12 hours for 6 weeks plus gentamicin.
Neonates older than 7 days*: 50,000 units/kg/dose IV or IM every 8 hours for 6 weeks plus gentamicin.
Infants, Children, and Adolescents: 200,000 to 300,000 units/kg/day (Max: 24 million units/day) IV or IM divided every 4 hours for 6 weeks plus gentamicin. The FDA-approved dose is 150,000 to 300,000 units/kg/day IV or IM divided every 4 to 6 hours.
-for the treatment of native or prosthetic valve endocarditis due to Enterococcus sp.*:
Intravenous or Intramuscular dosage:
Neonates 0 to 7 days: 50,000 units/kg/dose IV or IM every 12 hours for 4 to 6 weeks plus gentamicin.
Neonates older than 7 days: 50,000 units/kg/dose IV or IM every 8 hours for 4 to 6 weeks plus gentamicin.
Infants, Children, and Adolescents: 200,000 to 300,000 units/kg/day (Max: 24 million units/day) IV or IM divided every 4 hours for 4 to 6 weeks plus gentamicin.
-for the treatment of native valve endocarditis due to susceptible Staphylococcus sp.*:
Intravenous or Intramuscular dosage:
Neonates 0 to 7 days: 50,000 units/kg/dose IV or IM every 12 hours for 4 to 6 weeks; consider the addition of gentamicin for 3 to 5 days.
Neonates older than 7 days: 50,000 units/kg/dose IV or IM every 8 hours for 4 to 6 weeks; consider the addition of gentamicin for 3 to 5 days.
Infants, Children, and Adolescents: 200,000 to 300,000 units/kg/day (Max: 24 million units/day) IV or IM divided every 4 hours for 4 to 6 weeks; consider the addition of gentamicin for 3 to 5 days.
-for the treatment of prosthetic valve endocarditis due to susceptible Staphylococcus sp.*:
Intravenous or Intramuscular dosage:
Neonates 0 to 7 days: 50,000 units/kg/dose IV or IM every 12 hours plus rifampin for at least 6 weeks and gentamicin for 2 weeks.
Neonates older than 7 days: 50,000 units/kg/dose IV or IM every 8 hours plus rifampin for at least 6 weeks and gentamicin for 2 weeks.
Infants, Children, and Adolescents: 200,000 to 300,000 units/kg/day (Max: 24 million units/day) IV or IM divided every 4 hours plus rifampin for at least 6 weeks and gentamicin for 2 weeks.
-for the treatment of endocarditis due to S. moniliformis or S. minus (rat-bite or Haverhill fever):
Intravenous or Intramuscular dosage:
Infants, Children, and Adolescents: 150,000 to 250,000 units/kg/day (Max: 20 million units/day) IV or IM divided every 4 to 6 hours with or without streptomycin or gentamicin for at least 4 weeks.

For the treatment of meningitis and ventriculitis*:
NOTE: For gonococcal meningitis, see gonococcal infections. For neurologic Lyme infections, see Lyme borreliosis.
-for the treatment of Listeria meningitis*:
Intravenous dosage:
Neonates 0 to 7 days: 150,000 units/kg/dose IV every 8 hours for at least 21 days; consider the addition of an aminoglycoside.
Neonates older than 7 days: 125,000 units/kg/dose IV every 6 hours for at least 21 days; consider the addition of an aminoglycoside.
Infants, Children, and Adolescents: 300,000 to 400,000 units/kg/day (Max: 24 million units/day) IV divided every 4 to 6 hours for at least 21 days; consider the addition of an aminoglycoside.
-for the treatment of meningococcal meningitis:
Intravenous or Intramuscular dosage:
Neonates 0 to 7 days*: 150,000 units/kg/dose IV every 8 hours for 7 days.
Neonates older than 7 days*: 125,000 units/kg/dose IV every 6 hours for 7 days.
Infants, Children, and Adolescents: 300,000 to 400,000 units/kg/day (Max: 24 million units/day) IV divided every 4 to 6 hours for 7 days. The FDA-approved dose is 250,000 units/kg/day (Max: 20 million units/day) IV or IM divided every 4 hours for 7 to 14 days.
-for the treatment of pneumococcal meningitis or ventriculitis*:
Intravenous or Intramuscular dosage:
Neonates 0 to 7 days*: 150,000 units/kg/dose IV every 8 hours for 10 to 14 days.
Neonates older than 7 days*: 125,000 units/kg/dose IV every 6 hours for 10 to 14 days.
Infants, Children, and Adolescents: 300,000 to 400,000 units/kg/day (Max: 24 million units/day) IV divided every 4 to 6 hours for 10 to 14 days. The FDA-approved dose is 250,000 units/kg/day (Max: 20 million units/day) IV or IM divided every 4 hours for 7 to 14 days.
-for the treatment of beta-hemolytic streptococcal meningitis*:
Intravenous dosage:
Neonates 0 to 7 days: 150,000 units/kg/dose IV divided every 8 hours. Treat S. agalactiae for 14 to 21 days; consider the addition of an aminoglycoside.
Neonates older than 7 days: 125,000 units/kg/dose IV every 6 hours. Treat S. agalactiae for 14 to 21 days; consider the addition of an aminoglycoside.
Infants, Children, and Adolescents: 300,000 to 400,000 units/kg/day (Max: 24 million units/day) IV divided every 4 to 6 hours. Treat S. agalactiae for 14 to 21 days; consider the addition of an aminoglycoside.
-for the treatment of meningitis or ventriculitis due to C. acnes*:
Intravenous dosage:
Infants, Children, and Adolescents: 300,000 to 400,000 units/kg/day (Max: 24 million units/day) IV divided every 4 to 6 hours for 10 to 14 days.

For the treatment of disseminated gonorrhea:
-for the treatment of gonococcal arthritis:
Intravenous or Intramuscular dosage:
Infants, Children, and Adolescents weighing less than 45 kg: Not recommended by guidelines. 100,000 units/kg/day IV or IM divided every 6 hours for 7 to 10 days.
Children and Adolescents weighing 45 kg or more: Not recommended by guidelines. 10 million units/day IV or IM doses every 6 hours for 7 to 10 days.
-for the treatment of gonococcal endocarditis:
Intravenous or Intramuscular dosage:
Infants, Children, and Adolescents weighing less than 45 kg: Not recommended by guidelines. 250,000 units/kg/day IV or IM divided every 4 hours for 4 weeks.
Children and Adolescents weighing 45 kg or more: Not recommended by guidelines. 10 million units/day IV or IM divided every 6 hours for 4 weeks.
-for the treatment of gonococcal meningitis:
Intravenous or Intramuscular dosage:
Infants, Children, and Adolescents weighing less than 45 kg: Not recommended by guidelines. 250,000 units/kg/day IV or IM divided every 4 hours for 10 to 14 days.
Children and Adolescents weighing 45 kg or more: Not recommended by guidelines. 10 million units/day IV or IM divided every 6 hours for 10 to 14 days.

For the treatment of neurologic Lyme disease*, including Lyme meningitis*, cranial neuropathy*, and radiculoneuropathy/radiculoneuritis*:
-for the treatment of neurologic Lyme disease* without parenchymal involvement, including Lyme meningitis*, cranial neuropathy*, and radiculoneuropathy/radiculoneuritis*:
Intravenous dosage:
Infants, Children, and Adolescents: 200,000 to 400,000 units/kg/day (Max: 18 to 24 million units/day) IV in divided doses every 4 hours until clinical improvement, then switch to oral stepdown therapy for a total of 14 to 21 days as an alternative. For acutely ill patients or prior to confirmation of Lyme neuroborreliosis, IV therapy is preferred with appropriate stepdown to oral treatment.
-for the treatment of neurologic Lyme disease* with parenchymal involvement of the brain or spinal cord:
Intravenous dosage:
Infants, Children, and Adolescents: 200,000 to 400,000 units/kg/day (Max: 18 to 24 million units/day) IV in divided doses every 4 hours for 14 to 28 days. IV therapy is preferred.

For the adjunctive treatment of diphtheria and to prevent establishment of carrier state:
Intravenous or Intramuscular dosage:
Infants, Children, and Adolescents: 100,000 to 250,000 units/kg/day (Max: 4 million units/day) IV or IM divided every 6 hours for 14 days as an adjunct to diphtheria antitoxin.

For the treatment of rat-bite fever or Haverhill fever:
NOTE: For endocarditis, see endocarditis indication.
Intravenous or Intramuscular dosage:
Infants, Children, and Adolescents: 20,000 to 50,000 units/kg/day IV or IM divided every 4 to 6 hours for at least 5 to 7 days followed by oral step-down therapy with penicillin V or ampicillin. The FDA-approved dosage is 150,000 to 250,000 units/kg/day (Max: 20 million units/day) IV or IM divided every 4 hours for at least 4 weeks.

For the treatment of syphilis, including congenital syphilis and neurosyphilis or syphilitic eye disease* (e.g., uveitis*, neuroretinitis*, or optic neuritis*):
-for the treatment of neurosyphilis or syphilitic eye disease* (e.g., uveitis*, neuroretinitis*, or optic neuritis*):
Intravenous or Intramuscular dosage:
Infants, Children, and Adolescents: 200,000 to 300,000 units/kg/day (Max: 24 million units/day) IV or IM divided every 4 to 6 hours for 10 to 14 days.
-for the treatment of congenital syphilis:
NOTE: Current guidelines should be consulted to determine the appropriate course of treatment in neonates born to mothers with syphilis. Therapy is based on physical examination, serum quantitative nontreponemal serologic titer, and whether or not the mother was treated properly before delivery.
Intravenous or Intramuscular dosage:
Neonates 0 to 7 days*: 50,000 units/kg/dose IV every 12 hours for a total treatment duration of 10 days. If more than 1 day of therapy is missed, the entire course should be restarted.
Neonates 8 days and older*: 50,000 units/kg/dose IV every 8 hours for a total treatment duration of 10 days. If more than 1 day of therapy is missed, the entire course should be restarted.
Infants and Children: 200,000 to 300,000 units/kg/day IV or IM divided every 4 to 6 hours for 10 days. FDA-labeling suggests a 10 to 14 day duration. A single follow-up dose of penicillin G benzathine can be considered after IV therapy. If more than 1 day of therapy is missed, the entire course should be restarted.

For the treatment of skin and skin structure infections*, including cellulitis*, erysipelas*, and necrotizing infections*:
-for the treatment of nonpurulent skin infections, such as cellulitis and erysipelas*:
Intravenous dosage:
Neonates 0 to 7 days: 50,000 units/kg/dose IV every 12 hours for 5 to 14 days.
Neonates older than 7 days: 50,000 units/kg/dose IV every 8 hours for 5 to 14 days.
Infants, Children, and Adolescents: 60,000 to 100,000 units/kg/dose (Max: 4 million units/dose) IV every 6 hours for 5 to 14 days.
-for the treatment of necrotizing infections of the skin, fascia, and muscle*:
Intravenous dosage:
Neonates 0 to 7 days: 50,000 units/kg/dose IV every 12 hours until further debridement is not necessary, the patient has improved clinically, and fever has been absent for 48 to 72 hours plus clindamycin for group A streptococcal or clostridial infections.
Neonates older than 7 days: 50,000 units/kg/dose IV every 8 hours until further debridement is not necessary, the patient has improved clinically, and fever has been absent for 48 to 72 hours plus clindamycin for group A streptococcal or clostridial infections.
Infants, Children, and Adolescents: 60,000 to 100,000 units/kg/dose (Max: 4 million units/dose) IV every 6 hours until further debridement is not necessary, the patient has improved clinically, and fever has been absent for 48 to 72 hours plus clindamycin for group A streptococcal or clostridial infections.

For the treatment of bacteremia or empyema:
Intravenous or Intramuscular dosage:
Neonates 0 to 7 days: 50,000 units/kg/dose IV or IM every 12 hours.
Neonates older than 7 days: 50,000 units/kg/dose IV or IM every 8 hours.
Infants, Children, and Adolescents: 100,000 to 300,000 units/kg/day IV or IM divided every 4 to 6 hours (Max: 24 million units/day).

For the treatment of leptospirosis*:
Intravenous dosage:
Infants, Children, and Adolescents: 50,000 to 100,000 units/kg/day (Max: 6 million units/day) IV divided every 4 to 6 hours for 7 to 10 days as first-line therapy for severe disease.

For postexposure anthrax prophylaxis*:
-for postexposure anthrax prophylaxis* after nonaerosol exposure (cutaneous or ingestion):
Intramuscular dosage:
Neonates 32 weeks gestation and older: 25,000 units/kg/dose IM every 12 hours for 7 days after exposure.
-for postexposure anthrax prophylaxis* after aerosol exposure:
Intramuscular dosage:
Neonates 32 weeks gestation and older: 25,000 units/kg/dose IM every 12 hours for 60 days after exposure.

Maximum Dosage Limits:
-Neonates
0 to 7 days: 150,000 units/kg/day IV/IM.
8 days and older: 200,000 units/kg/day IV/IM.
-Infants
300,000 units/kg/day IV/IM is FDA-approved maximum; up to 400,000 units/kg/day IV/IM has been used off-label.
-Children
300,000 units/kg/day IV/IM (Max: 24 million units/day) is FDA-approved maximum; up to 400,000 units/kg/day IV/IM (Max: 24 million units/day) has been used off-label.
-Adolescents
300,000 units/kg/day IV/IM (Max: 24 million units/day) is FDA-approved maximum; up to 400,000 units/kg/day IV/IM (Max: 24 million units/day) has been used off-label.

Patients with Hepatic Impairment Dosing
No dosage adjustment required. If hepatic impairment is in conjunction with renal impairment, dosage adjustments may be necessary.

Patients with Renal Impairment Dosing
The manufacturer recommends:
CrCl >= 10 ml/min/1.73m2 in patients with uremia: A full loading dose, then 50% of the usual dose given every 4-5 hours.
CrCl < 10 ml/min/1.73m2: A full loading dose, then 50% of the usual dose given every 8-12 hours.

Other guidelines in adult patients recommend:
CrCl > 50 ml/min: No dosage adjustment necessary.
CrCl 10-50 ml/min: Adjust the dose to 75% of the usual dose.
CrCl < 10 ml/min: Adjust the dose to 20-50% of the usual dose.

Intermittent hemodialysis
Hemodialysis has been shown to reduce penicillin G serum concentrations. Recommendations in adults suggest giving a normal loading dose and then give 25-50% of the normal dose at regular intervals or 50-100% of the normal dose every 8-12 hours. Administer the dose after dialysis on hemodialysis days.

Peritoneal dialysis
Recommendations in adults suggest dosing for a CrCl < 10 ml/min by adjusting the dose to 20-50% of the usual dose.

Continuous renal replacement therapy
Recommendations in adults suggest dosing for a CrCl of 10-50 ml/min by adjusting the dose to 75% of the usual dose.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Penicillin G is a beta-lactam antibiotic. It is mainly bactericidal in action. It inhibits the third and final stage of bacterial cell wall synthesis by preferentially binding to specific penicillin-binding proteins (PBPs) located inside the bacterial cell wall. Penicillin-binding proteins are responsible for several different steps in the synthesis of the cell wall and are found in quantities of several hundred to several thousand molecules per bacterial cell. Penicillin-binding proteins vary among different bacterial species. Thus, the intrinsic activity of penicillin G, as well as the other penicillins, against a particular organism depends on its ability to gain access to and bind with the necessary PBP. Like all beta-lactam antibiotics, penicillin G's ability to interfere with PBP-mediated cell wall synthesis ultimately leads to cell lysis. Lysis is mediated by bacterial cell wall autolytic enzymes (i.e., autolysins). The relationship between PBPs and autolysins is unclear, but it is possible that the beta-lactam antibiotic interferes with an autolysin inhibitor.

Beta-lactams exhibit concentration-independent or time-dependent killing. In vitro and in vivo animal studies have demonstrated that the major pharmacodynamic parameter that determines efficacy for beta-lactams is the amount of time free (non-protein bound) drug concentrations exceed the minimum inhibitory concentration (MIC) of the organism. This microbiological killing pattern is due to the mechanism of action, which is acylation of PBPs. There is a maximum proportion of PBPs that can be acylated; therefore, once maximum acylation has occurred, killing rates cannot increase. Free beta-lactam concentrations do not have to remain above the MIC for the entire dosing interval.

The susceptibility interpretive criteria for penicillin are delineated by pathogen. The MICs are defined for S. pneumoniae in cases with meningitis as susceptible at 0.06 mcg/mL or less and resistant at 0.12 mcg/mL or more; use of penicillin in S. pneumonia in cases with meningitis requires a dose of at least 3 million units IV every 4 hours in adults with normal renal function. The MICs are defined for S. pneumoniae in cases without meningitis as susceptible at 2 mcg/mL or less, intermediate at 4 mcg/mL, and resistant at 8 mcg/mL or more; susceptible non-meningitis S. pneumonia strains can be treated with a dose of at least 2 million units IV every 4 hours in adults with normal renal function; strains with intermediate susceptibility may necessitate a penicillin dose of 18 to 24 million units IV per day. The MICs are defined for beta-hemolytic Streptococcus sp. as susceptible at 0.12 mcg/mL or less. The MICs are defined for Enterococcus sp. as susceptible at 8 mcg/mL or less and resistant at 16 mcg/mL or more. The MICs are defined for Staphylococcus sp. as susceptible at 0.12 mcg/mL or less and resistant at 0.25 mcg/mL or more. The MICs are defined for Streptococcus sp. Viridans group as susceptible at 0.12 mcg/mL or less, intermediate at 0.25 to 2 mcg/mL, and resistant at 4 mcg/mL or more. The MICs are defined for N. gonorrhoeae as susceptible at 0.06 mcg/mL or less, intermediate at 0.12 to 1 mcg/mL, and resistant at 2 mcg/mL or more. The MICs are defined for N. meningitidis as susceptible at 0.6 mcg/mL or less, intermediate at 0.12 to 0.25 mcg/mL, and resistant at 0.5 mcg/mL or more. The MICs are defined for anaerobes as susceptible at 0.5 mcg/mL or less, intermediate at 1 mcg/mL, and resistant at 2 mcg/mL or more. The MICs are defined for Abiotrophia sp., Granulicatella sp., Aerococcus sp., Corynebacterium sp., Gemella sp., and R. mucilaginosa as susceptible at 0.12 mcg/mL or less, intermediate at 0.25 mcg/mL to 2 mcg/mL, and resistant at 4 mcg/mL or more. The MICs are defined for Leuconostoc sp., Lactobacillus sp., and Pediococcus sp. as susceptible at 8 mcg/mL or less. The MICs are defined for L. monocytogenes as susceptible at 2 mcg/mL or less. The MICs are defined for Lactococcus sp., Aggregatibacter sp., Cardiobacter sp., E. corrodens, and Kingella sp. as susceptible at 1 mcg/mL or less, intermediate at 2 mcg/mL, and resistant at 4 mcg/mL or more. The MICs are defined for B. anthracis as susceptible at 0.5 mcg/mL or less and resistant at 1 mcg/mL or more. The MICs are defined for Micrococcus sp. and Bacillus sp. (excluding B. anthracis) as susceptible at 0.12 mcg/mL or less and resistant at 0.25 mcg/mL or more. The MICs are defined for E. rhusiopathiae as susceptible at 0.12 mcg/mL or less. The MICs are defined for Pasteurella sp. as susceptible at 0.5 mcg/mL or less.

Pharmacokinetics: Penicillin G sodium or potassium are administered by continuous or intermittent IV infusion or by IM injection. The pharmacokinetic parameters of penicillin G sodium and penicillin G potassium are the same. Approximately 45-68% of the circulating penicillin is protein-bound, mainly to albumin. It is distributed into most body tissues including lung, liver, kidney, bone, and muscle. In the presence of inflammation, penicillin penetrated abscesses and the middle ear as well as and peritoneal, pleural, and synovial fluids. Penetration into the eye, brain, CSF, and prostate are poor in the absence of inflammation. In the presence of inflamed meninges, the CSF:serum ratio is 2-6%. Inflammation also enhances penetration into the pericardial fluid. Penicillin G is actively secreted into the bile resulting in concentrations at least 10 times those achieved in serum. Penicillin crosses the placenta and is distributed in breast milk.

Penicillin G is excreted into the urine primarily via tubular secretion with 58-85% of the drug recovered in the urine. Nonrenal clearance includes hepatic metabolism and, to a lesser extend, biliary excretion which becomes more important with renal impairment.

Affected cytochrome P450 isoenzymes: none


-Route-Specific Pharmacokinetics
Intravenous Route
After intravenous infusion, peak penicillin G serum concentrations are attained immediately after completion of the infusion.

Intramuscular Route
After intramuscular administration, peak penicillin G concentrations occur rapidly.


-Special Populations
Pediatrics
Premature Neonates
Renal clearance of penicillin is delayed in premature neonates due to, comparatively, decreased renal function. In a study of 18 of neonates with gestational ages < 28 weeks and birth weights of < 1200 g, at doses of 50,000 units/kg IV every 12 hours (n=9), the serum peak (median 145.5 mcg/ml), trough, and AUC values were substantially greater than those reported in adults and older children. Therefore, a second group was studied at a dose of 25,000 units/kg IV every 12 hours (n=9) with proportionally lower values (median peak 58.9 mcg/ml); however with trough concentrations well above the MIC for group B Streptococcus. The median half-life was similar between the groups with a median value of 4.1 hours. In another study (n=20) in neonates with a gestational age of less than 32 weeks (average weight of 1195 g; range 650-2030 g) administered a dose of penicillin G 50,000 units/kg IV every 12 hours, the half-life was 3.9 hours and clearance increased significantly with increasing body weight (p<0.01).

Neonates
Renal clearance of penicillin is delayed in neonates due to, comparatively, decreased renal function. The half-life of penicillin G is 3.2 hours in neonates <= 6 days and decreases to 1.4 hours in those 14 days or older. At doses of 25,000 units/kg IV every 12 hours produced a mean peak serum concentration of 22 mcg/ml in the patients <= 6 days and 22.3 mcg/ml in patients > 7 days. At doses of 16,650 units/kg IV every 8 hours, mean peak serum concentrations was 24.6 mcg/ml for patients <= 6 days, 15.9 mcg/ml for patients 7-13 days, and 14 mcg/ml for patient > 14 days.

Infants, Children, and Adolescents
In a study of pediatric patients 1 month to 14 years (n=13) treated with penicillin G 200,000 units/kg/day in 6 divided doses administered over 20 minutes for pneumonia, the mean half-life was 1.21 hours with a mean peak serum concentration of 21.8 mcg/ml. The mean pleural fluid concentration was 10.9 mcg/ml. In adults, the mean half-life is 42 minutes and the mean peak serum concentration is 45 mcg/ml after 1 million units administered IV over 60 minutes.

Hepatic Impairment
In patients with altered renal function, the presence of hepatic insufficiency further reduces the elimination of penicillin G.

Renal Impairment
The elimination half-life of penicillin G increases as renal function declines. A linear relationship is found between the serum elimination rate constant and renal function as measured by creatinine clearance. The serum half-life has increased as high as 20 hours in anuric patients. In patients with altered renal function, the presence of hepatic insufficiency further alters elimination of penicillin G. In adult patients, the serum half-life in anuric patients with hepatic disease has been as high as 30.5 hours. Penicillin G is removed by hemodialysis.