Penicillin G  is a short-acting antibiotic that is administered intravenously or intramuscularly. It is used to treat skin infections, tetanus, and pneumonia.

Indications of Penicillin G

• Anthrax:

  • It is indicated for the treatment of anthrax caused by Bacillus anthracis.

• Actinomycosis:

  • It is prescribed for the management of actinomycosis (cervicofacial disease and thoracic and abdominal disease) caused by Actinomyces israelii.

• Clostridial infections:

  • Treatment of botulism concurrently with antitoxin, gas gangrene, and tetanus (adjunctive therapy to human tetanus immune globulin) caused by Clostridium spp is successfully done by penicillin G.

• Diphtheria:

  • It is prescribed for treating diphtheria concurrently antitoxin and prevention of the carrier state caused by Corynebacterium diphtheriae.

• Erysipelothrix endocarditis:

  • Treatment of erysipelothrix endocarditis caused by Erysipelothrix rhusiopathiae can be done by Penicillin G.

• Fusospirochetosis:

  • Treatment of fusospirochetosis, including severe infections of the oropharynx (Vincent), lower respiratory tract and genital area, caused by Fusobacterium spp. and spirochetes requires Penicillin G.

• Listeria infections:

  • It can be used for the treatment of listeria infections, including meningitis and endocarditis.

• Meningococcal infection:

  • Treatment of meningococcal meningitis and/or septicemia caused by Neisseria meningitidis can be done by penicillin G.

• Pasteurella infections:

  • Penicillin G is indicated for the treatment of pasteurella infections, including bacteremia and meningitis, caused by Pasteurella multocida

• Rat-bite fever:

  • It is also used for the treatment of rat-bite fever (including Haverhill fever) caused by Spirillum minus or S. moniliformis.

• Serious gram-positive infections:

  • Treatment of septicemia, empyema, pneumonia, pericarditis, endocarditis, and meningitis caused by Streptococcus pyogenes (group A beta-hemolytic streptococcus), other beta-hemolytic streptococci including groups C, H, G, L and M, Streptococcus pneumoniae and Staphylococcus species (nonpenicillinase-producing strains).

• Syphilis:

  • Treatment of syphilis (congenital and neurosyphilis) caused by Treponema pallidum can be done by penicillin G.

• Off Label Use of Penicillin G Adult:

  • Cutibacterium acnes infection of deep-brain stimulation hardware;
  • Group B streptococcus, maternal dose (neonatal prophylaxis);
  • Leptospirosis;
  • Lyme neuroborreliosis;
  • Osteomyelitis, native vertebral;
  • Prosthetic joint infection;
  • Skin and soft tissue infections;
  • Whipple Disease

Penicillin G dosage in adults:

Penicillin G Usual dosage range:

• 12 to 24 million units/day IM or IV in divided doses every 4 to 6 hours.

Indication-specific dosing:

• Actinomyces species:

  • Cervicofacial disease:

    • 1 to 6 million units intravenous in divided doses every 4 to 6 hours.

  • Thoracic and abdominal disease:

    • 10 to 20 million units/day intravenous in divided doses every 4 to 6 hours.

  • Anthrax:

    • Minimum 8 million units/day intravenous in divided doses every 6 hours; higher doses may be required depending on the susceptibility of the organism.

• Clostridium species:

  • Botulism, gas gangrene, tetanus:

    • 20 million units/day intravenous in divided doses every 4 to 6 hours; adjunctive therapies with botulinum antitoxin, tetanus immune globulin) are also recommended.

Penicillin G for Skin and soft tissue necrotizing infections (off-label):

• 2 to 4 million units every 4 to 6 hours concurrently with clindamycin and continue until further debridement is not necessary, the patient has clinically improved and is afebrile for 48 to 72 hours.

Penicillin G dose for Cutibacterium acnes infection of deep-brain stimulation hardware (off-label):

• 24 million units/day intravenous in divided doses every 4 hours.

Penicillin G for Diphtheria (adjunctive therapy to antitoxin and for prevention of carrier state):

• 2 to 3 million units/day intravenous in divided doses every 4 to 6 hours for 10 to 12 days.

Penicillin G dose in Endocarditis:

• Enterococcus, native or prosthetic valve (penicillin-susceptible/gentamicin-susceptible strains) (off-label dose):

  • 18 to 30 million units/day as a continuous infusion or in divided doses every 4 hours with concomitant gentamicin.
  • Duration of therapy: 4 weeks (native valve and symptoms present <3 months); 6 weeks (native valve and symptoms present ≥3 months or prosthetic valve).

• Enterococcus, native or prosthetic valve (penicillin-susceptible/ streptomycin susceptible/gentamicin-resistant strains) (off-label dose):

  • 18 to 30 million units/day intravenous as a continuous infusion or in divided doses every 4 hours with concomitant streptomycin.
  • Duration of therapy: 4 weeks (native valve and symptoms present <3 months); ≥6 weeks (native valve and symptoms present ≥3 months or prosthetic valve).

• Erysipelothrix rhusiopathiae:

  • 12 to 20 million units/day intravenous in divided doses every 4 to 6 hours for 4 to 6 weeks.

• Listeria monocytogenes:

  • 15 to 20 million units/day intravenous in divided doses every 4 to 6 hours for 4 weeks.

• Viridans group streptococcus (VGS) and S. bovis (off-label dose):

  • Native valve:

    • Highly penicillin-susceptible (MIC ≤0.12 mcg/mL): 12 to 18 million units/day as a continuous infusion or in divided doses every 4 or 6 hours for 4 weeks or 12 to 18 million units/day as a continuous infusion or in divided doses every 6 hours for 2 weeks with concomitant gentamicin.

  • Native valve:

    • Relatively penicillin-resistant (MIC >0.12 to <0.5 mcg/mL): 24 million units/day as a continuous infusion or in divided doses every 4 or 6 hours for 4 weeks with concomitant gentamicin for the first 2 weeks.

  • Prosthetic valve:

    • Highly penicillin-susceptible (MIC ≤0.12 mcg/mL): 24 million units/day as a continuous infusion or in divided doses every 4 or 6 hours for 6 weeks (with or without concomitant gentamicin for the first 2 weeks).

  • Prosthetic valve:

    • Relatively or fully penicillin-resistant (MIC >0.12 mcg/mL): 24 million units/day as continuous infusion or in divided doses every 4 or 6 hours with concomitant gentamicin for 6 weeks.

• Fusospirochetosis (including Vincent disease):

  • 5 to 10 million units/day intravenous in divided doses every 4 to 6 hours.

Penicillin G dose in Leptospirosis (off-label):

• 1.5 million units intravenous every 6 hours for 7 days.

Penicillin G dose in Lyme neuroborreliosis (off-label):

• 3 to 4 million units intravenous every 4 hours.

Penicillin G dose in bacterial Meningitis:

• As a component of pathogen-specific therapy (eg, Listeria monocytogenes, Neisseria meningitidis [with MIC <0.1 mcg/mL], Cutibacterium acnes, Streptococcus agalactiae, or Streptococcus pneumoniae [with MIC ≤0.06 mcg/mL]):

  • 4 million units intravenous every 4 hours. In patients with meningitis due to Listeria, combination with an aminoglycoside is recommended.

Penicillin G dose in Neurosyphilis (including ocular syphilis):

• 18 to 24 million units/day intravenous in divided doses every 4 hours (or by continuous infusion) for 10 to 14 days.

Penicillin G dose in native vertebral Osteomyelitis:

• Enterococcus spp (penicillin-susceptible) or streptococci (beta-hemolytic):

  • 20 to 24 million units/day intravenous as a continuous infusion or in divided doses every 4 hours for 6 weeks.
  • Note: In patients with infective endocarditis due to penicillin-susceptible Enterococcus spp, the addition of an aminoglycoside for 4 to 6 weeks is recommended.

• Cutibacterium acnes:

  • 20 million units/day as a continuous infusion or in divided doses every 4 hours for 6 weeks

Penicillin G dose in Bacteremia and meningitis caused by Pasteurella infections:

• • 4 to 6 million units/day intravenous in divided doses every 4 to 6 hours for 2 weeks.

Penicillin G dose in Prosthetic joint infection (off-label): 

• Penicillin-susceptible Enterococcus spp, streptococci (beta-hemolytic):

  • 20 to 24 million units/day intravenous as a continuous infusion every 24 hours or in divided doses every 4 hours for 4 to 6 weeks.
  • Note: For penicillin-susceptible Enterococcus spp, consider the addition of aminoglycoside.

• Cutibacterium acnes:

  • 20 million units/day intravenous as a continuous infusion every 24 hours or in divided doses every 4 hours for 4 to 6 weeks.

Penicillin G dose in Rat bite fever (including Haverhill fever):

• Uncomplicated infection:

  • 200,000 units intravenous every 4 hours for 5 to 7 days;
  • if the patient clinically improves after an initial IV course, switch to oral therapy (eg, penicillin V or amoxicillin) to complete a 14-day course.

• Serious invasive infection:

  • 12 to 18 million units/day as a continuous infusion every 24 hours or in divided doses every 4 to 6 hours for 4 weeks; may increase the dose to 24 million units/day in patients with an isolate that is not highly penicillin-susceptible.

Penicillin G dose in Streptococcus infections:

• Maternal dose for neonatal prophylaxis (Group B streptococcus):

  • 5 million units intravenous x 1 dose, then 2.5 to 3 million units every 4 hours until delivery.

• Skin infections, including skin and soft tissue necrotizing infections (off-label use):

  • 2 to 4 million intravenous units every 4 to 6 hours;
  • use in combination with clindamycin for necrotizing infections and continue until further debridement is not necessary, the patient has clinically improved, and the patient is afebrile for 48 to 72 hours.

• Severe Group A streptococcus invasive infection:

  • 3 to 4 million units intravenous every 4 hours with clindamycin for 10 to 14 days.

• Streptococcal pneumonia:

  • 2 to 24 million units/day intravenous in divided doses every 4 to 6 hours.
  • Note: Only recommended for S. pneumoniae when MIC is <2 mcg/mL.

Penicillin G dose in Whipple disease (off-label):

• 2 to 4 million units intravenous every 4 hours for 2 to 4 weeks, followed by oral trimethoprim/sulfamethoxazole monotherapy or oral doxycycline and hydroxychloroquine for 1 year.

Penicillin G dose in children:

General dosing in susceptible infections:

• Mild to moderate infection:

  • 100,000 to 150,000 units/kg/day IM or IV in divided doses every 6 hours.
  • The maximum daily dose: 8 million units/day

• Severe infections:

  • 200,000 to 300,000 units/kg/day IM or IV in divided doses every 4 to 6 hours.
  • The maximum daily dose: 24 million units/day.
  • Note: Use the highest dose in range for CNS infections.

Penicillin G dose in systemic Anthrax:

• Non-CNS infection; preferred agent for penicillin-susceptible strains:

  • 400,000 units/kg/day intravenous in divided doses every 4 hours.
  • The maximum dose: 4 million units/dose use in combination with clindamycin, linezolid, doxycycline, or rifampin for ≥14 days until clinical stability is achieved (ie, appear well with no signs or symptoms of active infection and can tolerate oral therapy), treatment must be followed by prophylaxis for a total antibiotic course of 60 days.

• Meningitis; preferred agent for penicillin-susceptible strains:

  • 400,000 units/kg/day intravenous in divided doses every 4 hours;
  • The maximum dose: 4 million units/dose; use in combination with a fluoroquinolone plus linezolid, clindamycin, rifampin, or chloramphenicol for ≥2 to 3 weeks until clinical stability is achieved (ie, appear well with no signs or symptoms of active infection and can tolerate oral therapy);
  • The treatment must be followed by prophylaxis for a total antibiotic course of 60 days.

Penicillin G treatment for Clostridial myonecrosis (gas gangrene):

• 250,000 to 400,000 units/kg/day intravenous in divided doses every 4 to 6 hours with or without clindamycin.

Penicillin G dose in Diphtheria:

• 150,000 to 250,000 units/kg/day IM/ IV in divided doses every 6 hours for 7 to 10 days.
• AAP suggests a duration of 14 days.

Penicillin G dose in bacterial Endocarditis:

• 200,000 to 300,000 units/kg/day intravenous in divided doses every 4 hours.
• The maximum daily dose: 24 million units/day, treat for at least 4 weeks; longer duration may be necessary;
• It may be used in combination with gentamicin for some resistant organisms.
• Note: For endocarditis from rat-bite fever/ haverhill fever, the manufacturer recommends a lower dose of 150,000 to 250,000 units/kg/day in divided doses every 4 hours.
• The maximum daily dose: 20 million units/day.

Penicillin G dose in Lyme disease:

• 200,000 to 400,000 units/kg/day intravenous in divided doses every 4 hours.
• The maximum daily dose: 24 million units/day.

Penicillin G dose in the treatment of Meningitis:

Note: Dosing varies based on the organism being treated.

• Group B streptococcus:

  • Infants: 450,000 to 500,000 units/kg/day intravenous divided every 6 hours.

• Strep. pneumoniae:

  • 250,000 to 400,000 units/kg/day intravenous divided every 4 to 6 hours.

• Other susceptible organisms:

  • 300,000 units/kg/day intravenous divided every 4 to 6 hours
  • The maximum daily dose: 24 million units/day.

• Meningococcal disease:

  • 300,000 units/kg/day intravenous in divided doses every 4 to 6 hours.
  • The maximum daily dose: 12 million units/day.

Penicillin G dose in community-acquired Pneumonia:

• Empiric treatment or S. pneumoniae (moderate to severe; MICs to penicillin ≤2.0 mcg/mL):

  • 200,000 to 250,000 units/kg/day intravenous divided every 4 to 6 hours.

  • Alternate dosing:

    • 250,000 to 400,000 units/kg/day intravenous divided every 4 to 6 hours.

  • Group A Streptococcus (moderate to severe):

    • 100,000 to 250,000 units/kg/day intravenous divided every 4 to 6 hours.

Penicillin G dose in Skin and soft tissue necrotizing infections due to Clostridium species:

• 60,000 to 100,000 units/kg/dose intravenous every 6 hours;
• Use in combination with clindamycin and continue until further debridement is not necessary, the patient has clinically improved, and the patient is afebrile for 48 to 72 hours.

Dose in Streptococcal skin infections, including skin and soft tissue necrotizing infections:

• 60,000 to 100,000 units/kg/dose intravenous every 6 hours.
• The maximum dose: 4 million units/dose in combination with clindamycin for necrotizing infections and continue until further debridement is not necessary, the patient has clinically improved, and the patient is afebrile for 48 to 72 hours.

Penicillin G dose in Congenital Syphilis:

• 50,000 units/kg/dose intravenous every 4 to 6 hours for 10 days.

Penicillin G dose in Neurosyphilis (including ocular syphilis):

• Infants and Children:

  • 50,000 units/kg/dose intravenous every 4 to 6 hours for 10 to 14 days.
  • The maximum daily dose: 24 million units/day.

• Adolescents:

  • 3 to 4 million units intravenous every 4 hours or as a continuous infusion for 10 to 14 days.
  • The maximum daily dose: 24 million units/day.

Penicillin G dose in Tetanus:

• 100,000 units/kg/day intravenous in divided doses every 4 to 6 hours for 7 to 10 days.
• The maximum daily dose: 12 million units/day.

Pregnancy Risk Category: B

• Penicillin has the ability to cross placenta although adverse fetal effects have not been reported.
• Penicillin G is the drug of choice for treatment of syphilis during pregnancy and for the prevention of early-onset Group B Streptococcal disease in newborns.
• It can be used as an alternate agent for anthrax infection in pregnancy and postpartum.

Penicillin G use during breastfeeding:

• Penicillin G is excreted in breast milk therefore the manufacturer recommends that it should be cautiously used in breastfeeding women.
• Peak milk concentrations occur at approximately 1 hour after an IM dose and are higher if multiple doses are given.
• Allergic reactions and the modification of bowel flora can occur.

Dose adjustment in renal disease:

• Manufacturer's labeling:

  • Uremic patients with Creatinine clearance >10 mL/minute/1.73 m²:

    • Administer a usual recommended dose followed by a 50% dose reduction every 4 to 5 hours.

  • Creatinine clearance <10 mL/minute/1.73 m²:

    • Administer a normal dose followed by a 50% dose reduction every 8 to 10 hours.

• Alternate recommendation:

  • GFR >50 mL/minute:

    • No dosage adjustment necessary.

  • GFR 10-50 mL/minute:

    • Administer 75% of the normal dose.

  • GFR <10 mL/minute:

    • Administer 20% to 50% of the normal dose.

  • End-stage renal disease on intermittent hemodialysis:

    • 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 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:

  • Drug clearance is dependent on the filter type, flow rate or method of renal replacement.
  • Close monitoring of adverse reactions due to drug accumulation, pharmacologic response, drug concentrations in relation to target trough is needed for appropriate dosing.
  • 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:

    • A loading dose of 4 million units, followed by 2 million units every 4 to 6 hours.

  • CVVHD:

    • A loading dose of 4 million units, followed by 2 to 3 million units every 4 to 6 hours.

  • CVVHDF:

    • A loading dose of 4 million units, followed by 2 to 4 million units every 4 to 6 hours.

Dose adjustment in liver disease:

There are no dosage adjustments provided in the manufacturer's labeling. Dose adjustment is required in patients with both renal and hepatic impairment.

Side effects of Penicillin G:

• Cardiovascular:

  • Localized Phlebitis
  • Local Thrombophlebitis

• Central Nervous System:

  • Coma (High Doses)
  • Hyperreflexia (High Doses)
  • Myoclonus (High Doses)
  • Seizure (High Doses)

• Dermatologic:

  • Contact Dermatitis
  • Skin Rash

• Endocrine & Metabolic:

  • Electrolyte Disturbance (High Doses)

• Gastrointestinal:

  • Pseudomembranous Colitis

• Hematologic & Oncologic:

  • Neutropenia
  • Positive Direct Coombs Test (Rare
  • High Doses)

• Hypersensitivity:

  • Anaphylaxis
  • Hypersensitivity Reaction (Immediate And Delayed)
  • Serum Sickness

• Immunologic:

  • Jarisch-Herxheimer Reaction

• Local:

  • Injection Site Reaction

• Renal:

  • Acute Interstitial Nephritis (High Doses)
  • Renal Tubular Disease (High Doses)

Contraindications to Penicillin G:

Hypersensitivity to any penicillin or any component of the formulation Documentation of allergenic cross-reactivity for beta-lactams (eg, penicillins and cephalosporins) is limited, but the possibility of cross-sensitivity cannot be ruled because of similarities in chemical structure and/or pharmacologic actions.

Warnings and Precautions

• Anaphylactic and hypersensitivity reactions:

  • Serious and fatal hypersensitivity anaphylactic reactions can occur especially with a history of beta-lactam hypersensitivity (including cephalosporins) or history of sensitivity to multiple allergens.
  • Immediate discontinuation and supportive therapy should be given if a reaction occurs.
  • It should be cautiously used in asthmatic patients.

• Neurovascular damage:

  • Severe and permanent neurovascular damage can occur if penicillin G is given intra-arterial.

• Superinfection:

  • Fungal or bacterial superinfection such as C. difficile-associated diarrhea and pseudomembranous colitis can occur with prolonged therapy.

• Renal impairment:

  • Dose adjustment is required in concurrent renal and hepatic impairment.

• Seizure disorders:

  • In case of a renal impairment the risk of seizures can be increased with higher doses.

Penicillin G (intravenous and short-acting intramuscular): Drug Interaction

Risk Factor C (Monitor therapy)
Acemetacin	Could raise the serum level of penicillins.
BCG Vaccine (Immunization)	Antibiotics may reduce the BCG vaccine's therapeutic effect (Immunization).
Lactobacillus and Estriol	The therapeutic effects of Lactobacillus and Estriol may be reduced by antibiotics.
Methotrexate	Penicillins may raise the level of methotrexate in the serum.
Mycophenolate	The serum levels of the active metabolite(s) of mycophenolate may drop when penicillins are used. Enterohepatic recirculation appears to be hindered, which has this impact.
Nitisinone	OAT1/3 Substrates' serum concentration can rise.
Pretomanid	OAT1/3 Substrates' serum concentration can rise.
Probenecid	Could raise the serum level of penicillins.
Teriflunomide	OAT1/3 Substrates' serum concentration can rise.
Vitamin K Antagonists (eg, warfarin)	The anticoagulant impact of vitamin K antagonists may be strengthened by penicillins.
Risk Factor D (Consider therapy modification)
Sodium Picosulfate	Antibiotics may reduce Sodium Picosulfate's therapeutic impact. Management: If a patient previously used or is currently using an antibiotic, think about utilising an alternative product for bowel cleansing prior to a colonoscopy.
Tetracyclines	May reduce penicillins' therapeutic efficacy.
Tolvaptan	OAT1/3 Substrates' serum concentration can rise. Treatment: Patients taking the Jynarque brand of tolvaptan should refrain from taking OAT1/3 substrates concurrently. With any combined use, it would be predicted that OAT1/3 substrate concentrations and effects would rise.
Typhoid Vaccine	The Typhoid Vaccine's therapeutic benefits may be reduced by antibiotics. The only strain impacted is the live attenuated Ty21a strain. Treatment: Patients receiving systemic antibacterial drugs should refrain from receiving the live attenuated typhoid vaccination (Ty21a). This vaccine should not be used right away.
Risk Factor X (Avoid combination)
BCG (Intravesical)	Antibiotics may lessen BCG's therapeutic effects (Intravesical).
Cholera Vaccine	The therapeutic benefit of the cholera vaccine may be reduced by antibiotic use. Management: Cholera vaccine should not be administered to individuals taking systemic antibiotics or within 14 days after taking oral or parenteral antibiotics.

Monitoring parameters:

• Hematological functions
• Hepatic function tests
• Renal function tests
• Serum electrolytes
• Cardiac monitoring for prolonged therapy
• Signs and symptoms of anaphylaxis during first dose.
• Seizures in case of old age.

How to administer Penicillin G?

Intramuscular:

• Penicillin G is given as an intramuscular by deep injection in the upper outer quadrant of the buttock around the clock to promote less variation in peak and trough levels.

Intravenous:

• It is usually given as an intermittent infusion over 15 to 30 minutes. However,some centers give large doses by continuous Intravenous infusion.

Note:

• The 20 million unit dosage form may be administered by an Intravenous infusion only.

Mechanism of action of Penicillin G:

Penicillin G  causes cell death by interfering with bacterial cell wall synthesis during active multiplication and results in bactericidal activity against susceptible bacteria.

Distribution:

• Poor penetration across the blood-brain barrier, despite inflamed meninges.
• CSF:blood level ratio:: Inflamed meninges: 2% to 6%

Half-life elimination:

• Neonates: <6 days of age: 3.1 hours;
• ≥14 days of age: 1.4 hours
• Adults: Normal renal function: 31 to 50 minutes
• End-stage renal disease (ESRD): 6 to 20 hours (Aronoff 2007)

Excretion:

• Urine (58% to 85% as unchanged drug)

International Brands of Penicillin G:

• Pfizerpen
• Crystapen
• Benpen
• Pengesod
• Penicilina Northia
• Penicillin G
• Pisacilina
• Sodipen

Penicillin G Brands in Pakistan:

Brands in Pakistan will be updated later.