Penicillin G (Parenteral / Aqueous)

Excretion is delayed.

Renal clearance may be delayed (caused by decreased renal function).

Manufacturer's labeling:

Uremic patients with CrCl >10 mL/minute/1.73 m2: Administer a usual recommended dose followed by 50% of the usual recommended dose every 4 to 5 hours

CrCl <10 mL/minute/1.73 m2: Administer a normal dose followed by 50% of the normal dose every 8 to 10 hours

Alternate recommendation:

GFR >50 mL/minute: No dosage adjustment necessary (Aronoff 2007).

GFR 10-50 mL/minute: Administer 75% of the normal dose (Aronoff 2007).

GFR <10 mL/minute: Administer 20% to 50% of the normal dose (Aronoff 2007).

End-stage renal disease on intermittent hemodialysis (IHD) (administer after hemodialysis on dialysis days) (Heintz 2009): Administer a normal dose followed by either 25% to 50% of normal dose every 4 to 6 hours or 50% to 100% of normal dose every 8 to 12 hours. For mild-to-moderate infections, administer 0.5 to 1 million units every 4 to 6 hours or 1 to 2 million units every 8 to 12 hours. For neurosyphilis, endocarditis, or serious infections, administer up to 2 million units every 4 to 6 hours; administer after dialysis on dialysis days or supplement with 500,000 units after dialysis. Note: Dosing dependent on the assumption of 3 times weekly, complete IHD sessions.

Continuous renal replacement therapy (CRRT) (Heintz 2009; Trotman 2005): Drug clearance is highly dependent on the method of renal replacement, filter type, and flow rate. Appropriate dosing requires close monitoring of pharmacologic response, signs of adverse reactions due to drug accumulation, as well as drug concentrations in relation to target trough (if appropriate). The following are general recommendations only (based on dialysate flow/ultrafiltration rates of 1 to 2 L/hour and minimal residual renal function) and should not supersede clinical judgment:

CVVH: Loading dose of 4 million units, followed by 2 million units every 4 to 6 hours

CVVHD: Loading dose of 4 million units, followed by 2 to 3 million units every 4 to 6 hours

CVVHDF: Loading dose of 4 million units, followed by 2 to 4 million units every 4 to 6 hours

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Upset stomach or throwing up.
• Mouth irritation or mouth sores.
• Change in tongue color.
• Irritation where the shot is given.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Applies to penicillin g potassium: injectable powder for injection, intravenous solution

Hypersensitivity

Allergic reactions have been reported with all penicillins and the incidence ranged from 0.7% to 10% in studies.

Hypersensitivity reactions with penicillin are more common and more serious with intravenous therapy, but have also been reported with oral therapy. An initial sensitizing exposure is required to stimulate the production of antigen-specific IgE before clinical manifestations of hypersensitivity are seen on the second exposure. There are numerous "hidden" environmental or occupational exposures to penicillin including in utero exposure, breast milk exposure, and occupational exposure.

Immediate anaphylactic reactions were very rare and generally occurred after parenteral therapy; however, a few cases of anaphylaxis have been reported after oral therapy.

Delayed reactions to penicillin have been reported within 1 to 2 weeks after therapy was started.

The Jarisch-Herxheimer reaction has started 1 to 2 hours after initiation of therapy and has stopped within 12 to 24 hours. The Herxheimer reaction may be due to the release of heat-stable pyrogen from spirochetes.[Ref]

Hypersensitivity side effects have included immediate and delayed allergic reactions. Immediate reactions generally occurred within 20 minutes of use and the severity ranged from urticaria and pruritus to angioneurotic edema, laryngospasm, bronchospasm, hypotension, vascular collapse, and death. A different type of immediate reaction, an accelerated reaction, occurred 20 minutes to 48 hours after use and included urticaria, pruritus, fever, and, occasionally, laryngeal edema. Manifestations of delayed reactions to penicillin included serum sickness-like symptoms, i.e., fever, malaise, urticaria, myalgia, arthralgia, abdominal pain, and various skin rashes (ranging from maculopapular eruptions to exfoliative dermatitis). Hypersensitivity myocarditis, eosinophilia, allergic vasculitis, asthenia, pain, reactions resembling serum sickness (including chills, fever, edema, arthralgia, and prostration), and anaphylaxis (severe and occasionally fatal) have been reported. The Jarisch-Herxheimer reaction (characterized by fever, chills, myalgias, headache, exacerbation of cutaneous lesions, tachycardia, hyperventilation, vasodilation with flushing, and mild hypertension) has been reported during penicillin treatment of patients with syphilis or other spirochaetal infections.[Ref]

Cardiovascular

Cardiovascular side effects have included cardiac arrhythmias and cardiac arrest.[Ref]

Gastrointestinal

Gastrointestinal side effects have included Clostridium difficile associated diarrhea and pseudomembranous colitis; onset has occurred during or after therapy. Nausea, vomiting, diarrhea, stomatitis, black or hairy tongue, and other symptoms of gastrointestinal irritation have been reported, especially during oral therapy.[Ref]

Metabolic

Metabolic side effects have included serious and even fatal electrolyte disturbances (i.e., hyperkalemia) with large intravenous doses since 1 million units of penicillin G potassium contains 1.68 mEq of potassium ion. Severe or fatal potassium poisoning (signs included hyperreflexia, convulsions, and coma) has been reported in patients receiving continuous intravenous therapy in high doses (10 million to 100 million units/day), especially in the presence of renal insufficiency.[Ref]

Nervous system

Severe neurologic reactions were most often seen with penicillin doses of 18 million to 80 million units daily. These reactions frequently abated after discontinuation of penicillin. In several cases, penicillin was restarted at a lower dose with no further sequelae. In one review, the authors found that cerebral spinal fluid (CSF) penicillin levels were higher in patients with seizures than in those without. CSF penicillin levels ranged from 12 to 61 units/mL in the seizure group with the highest CSF concentrations, compared to 7.8 units/mL in the group without seizures.[Ref]

Nervous system side effects have rarely included neuropathy, which was usually associated with high intravenous dosage. Neurotoxic reactions (including hyperreflexia, myoclonic twitches, seizures, and coma) have been reported after massive intravenous doses were administered, and were more likely in patients with renal dysfunction. Severe reactions (including myoclonus, seizures, auditory and visual hallucinations, and decreased mentation) have been reported with high dose penicillin therapy or in patients with renal dysfunction. Neurologic reactions occurred frequently in patients with renal dysfunction. Neurovascular damage, headache, tremor, confusion, agitation, aseptic meningitis, and coma have been reported.[Ref]

Renal

Renal tubular damage and interstitial nephritis resolved in most patients after penicillin G was discontinued.

Nephropathy has been reported rarely and was usually associated with high intravenous dosage.[Ref]

Renal side effects associated with large intravenous doses of penicillin G have included renal tubular damage and interstitial nephritis. Symptoms of this reaction included fever, rash, eosinophilia, proteinuria, eosinophiluria, hematuria, and a rise in serum urea nitrogen. Increased BUN and creatinine, renal failure, and nephropathy have been reported.[Ref]

Hematologic

Hematologic side effects have included hemolytic anemia, anemia, leukopenia, neutropenia, thrombocytopenia, Coombs-positive hemolytic anemia, and a bleeding diathesis secondary to platelet dysfunction.[Ref]

Hemolytic anemia, leukopenia, and thrombocytopenia have been reported rarely and were usually associated with high intravenous dosage.

Neutropenia resolved after penicillin was discontinued.

Coombs-positive hemolytic anemia (an uncommon reaction) was reported in patients treated with greater than 10 million units/day of intravenous penicillin G and who previously received large doses of the drug.

A bleeding diathesis secondary to platelet dysfunction has been associated with large doses of penicillin.[Ref]

Local

Local side effects have included injection site pain with intravenous administration, phlebitis, thrombophlebitis, and neurovascular damage.[Ref]

Genitourinary

Genitourinary side effects have included hematuria, proteinuria, and eosinophiluria.[Ref]

Dermatologic

Dermatologic side effects have included rash and urticaria. Contact dermatitis has been reported in those who prepared penicillin solutions.[Ref]

Hepatic

A 28-year-old female developed jaundice, fever, epidermolysis, abnormal liver function tests, and cholestasis several days after receiving a single dose of penicillin intramuscularly. Her liver dysfunction continued for up to 18 months. She had taken acetaminophen concurrently but denied alcohol use.[Ref]

Hepatic side effects have included increased SGOT, reversible hepatotoxicity, jaundice, and prolonged cholestasis.[Ref]

Some side effects of penicillin g potassium may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Serious infections due to susceptible strains of streptococci: 12 million to 24 million units/day IV in divided doses every 4 to 6 hours, depending on the nature and severity of the infection

Serious infections due to susceptible strains of staphylococci: 5 million to 24 million units/day IV in divided doses every 4 to 6 hours, depending on the nature and severity of the infection

Erysipelothrix rhusiopathiae: 2 million to 20 million units/day IV in divided doses every 4 to 6 hours for 4 to 6 weeks

Listeria monocytogenes: 15 million to 20 million units/day IV in divided doses every 4 to 6 hours for 4 weeks

Meningococcal meningitis and/or septicemia: 1 million to 2 million units IM every 2 hours or 20 million to 30 million units/day as a continuous IV infusion for at least 10 to 14 days

If meningococcal meningitis is suspected, immediate treatment with penicillin is required, and should be started before lumbar puncture confirmation of the diagnosis. The mortality of this disease is 50% within the first 24 hours.

Treatment of penicillin-susceptible anthrax:
As the result of naturally occurring or endemic anthrax exposure: Minimum of 8 million units/day IV in divided doses every 6 hours; higher doses may be needed depending on susceptibility of organism

Dosages up to 20 million units/day IV have been used to treat anthrax septicemia and intestinal, pulmonary, and meningeal anthrax. Some clinicians recommend 8 million to 12 million units/day in divided doses every 4 to 6 hours for the treatment of anthrax due to natural or endemic anthrax exposures.

Duration: At least 14 days after symptoms abate

As the result of exposure to B anthracis spores during biologic warfare or bioterrorism: 4 million units IV every 4 hours; oral therapy may be substituted once the patient's clinical condition improves

Treatment of inhalation anthrax should be started with a multiple-drug parenteral regimen that includes ciprofloxacin or doxycycline plus 1 or 2 additional antibiotics with activity against the causative organism. A multiple-drug parenteral regimen is also recommended for initial treatment of cutaneous anthrax if there are signs of systemic involvement, extensive edema, or lesions on the head or neck. Due to concerns regarding resistance, penicillin alone is not recommended for inhalation anthrax that occurs as the result of biologic warfare or bioterrorism since high concentrations of the organism are expected, but it can be included in appropriate combination therapies.

Duration: 60 days (including IV and oral therapy)

Adjunctive therapy to antitoxin: 20 million units/day IV in divided doses every 4 to 6 hours

Wound botulism (as an adjunct to antitoxin, supportive care, and surgical debridement): 2 million units IV every 4 hours plus metronidazole 250 mg IV every 6 hours

Early Lyme disease with acute neurologic disease manifested by meningitis or radiculopathy: 18 million to 24 million units/day IV in divided doses every 4 hours

Late Lyme disease and associated neurologic disease affecting the CNS or peripheral nerve disease (e.g., neuropathy, encephalopathy) and documented by CSF analysis: 18 million to 24 million units/day IV in divided doses every 4 to 6 hours

Duration: 14 to 28 days

Penicillin G is recommended as an alternative to IV ceftriaxone. Ceftriaxone is considered the parenteral drug of choice.

1.5 million units IV every 6 hours for 7 days

2 million to 4 million units IV or IM every 4 to 6 hours for 2 to 3 weeks, depending on the nature and severity of the infection

The addition of metronidazole to high-dose penicillin therapy is recommended by many experts to treat parapharyngeal infections because of the increasing frequency of penicillin-resistant anaerobes. Removal of abscessed material is also necessary for successful treatment.

Erysipelas: 1 million to 2 million units IV every 4 to 6 hours
Streptococcal cellulitis: 1 million to 2 million units IV every 6 hours for 7 to 10 days

2 million to 3 million units IV every 4 to 6 hours plus metronidazole 500 mg IV every 8 hours for 7 to 14 days, depending on the nature and severity of the infection

American Academy of Pediatrics (AAP) recommendations:
Neonates:
7 days or less:
2000 g or less: 25,000 to 50,000 units/kg IM or IV every 12 hours
Greater than 2000 g: 25,000 to 50,000 units/kg IM or IV every 8 hours

Greater than 7 days:
Less than 1200 g: 25,000 to 50,000 units/kg IM or IV every 12 hours
1200 to 2000 g: 25,000 to 50,000 units/kg IM or IV every 8 hours
Greater than 2000 g: 25,000 to 50,000 units/kg IM or IV every 6 hours

Infants and children:
Mild to moderate infections: 100,000 to 250,000 units/kg/day IM or IV in divided doses every 4 to 6 hours
Severe infections: 250,000 to 400,000 units/kg/day IM or IV in 4 to 6 divided doses

Maximum dose: 24 million units/day

Manufacturers recommendation:
Serious infections, such as pneumonia and endocarditis, due to susceptible strains of streptococci (including S pneumoniae) and meningococcus: 150,000 to 300,000 units/kg/day IV in divided doses every 4 to 6 hours

The duration of therapy depends on the nature and severity of the infection.

Manufacturers recommendation: 250,000 units/kg/day IV in divided doses every 4 hours for 7 to 14 days, depending on the nature and severity of the infection

Maximum dose: 12 million to 20 million units/day

Manufacturers recommendation:
1 month or older: 50,000 units/kg IV every 4 to 6 hours for 10 to 14 days

CDC recommendation:
Adolescents: 3 million to 4 million units IV every 4 hours or 18 million to 24 million units/day as a continuous infusion for 10 to 14 days; many experts recommend additional therapy with penicillin G benzathine 2.4 million units IM once a week for up to 3 weeks following completion of IV therapy