Can you provide the indications, dosing, contraindications, adverse effects, and alternative therapies for Penicillin G?

Penicillin G: Clinical Overview

Indications

Penicillin G remains the drug of choice for serious streptococcal and syphilitic infections, with specific indications spanning from endocarditis to neurosyphilis. 1

Streptococcal Infections

• Highly penicillin-susceptible viridans group streptococci and Streptococcus bovis endocarditis (MIC ≤0.12 μg/mL): Aqueous crystalline penicillin G 12-18 million units/24h IV continuously or in 4-6 divided doses for 4 weeks 2
• Group A β-hemolytic streptococcal infections: Treatment must continue for at least 10 days to reduce rheumatic fever risk 1
• Pneumococcal pneumonia: Penicillin G remains the drug of choice for susceptible S. pneumoniae in the United States 2

Syphilis

• Primary, secondary, and early latent syphilis: Benzathine penicillin G 2.4 million units IM as a single dose 3, 4
• Late latent syphilis or syphilis of unknown duration: Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM at weekly intervals 3, 4
• Neurosyphilis: Aqueous crystalline penicillin G 18-24 million units/day IV (3-4 million units every 4 hours) for 10-14 days 2, 1
• Congenital syphilis: Aqueous crystalline penicillin G 100,000-150,000 U/kg/day IV (50,000 U/kg every 12 hours for first 7 days, then every 8 hours) for 10 days 2

Other Serious Infections

• Meningococcal meningitis and septicemia caused by Neisseria meningitidis 1
• Listeria monocytogenes infections including meningitis and endocarditis 1
• Disseminated gonococcal infections (penicillin-susceptible strains only) 1
• Diphtheria (adjunctive to antitoxin): 150,000-250,000 units/kg/day in divided doses every 6 hours for 7-10 days 1
• Tetanus (adjunctive to human tetanus immune globulin) 1

Dosing Regimens

Adult Dosing by Indication

For life-threatening pneumococcal pneumonia, a loading dose of 3 million units followed by continuous infusion of 10-12 million units every 12 hours provides optimal serum levels of 16-20 μg/mL. 5

Endocarditis

• Native valve, highly susceptible streptococci: 12-18 million units/24h IV continuously or in 4-6 divided doses for 4 weeks 2
• With gentamicin (2-week regimen): 12-18 million units/24h IV for 2 weeks plus gentamicin 3 mg/kg/24h for 2 weeks (not for patients with cardiac/extracardiac abscess, CrCl <20 mL/min, or eighth nerve dysfunction) 2

Meningitis

• Pediatric bacterial meningitis: 250,000 units/kg/day in equal doses every 4 hours for 10-14 days 1
• Adult dosing for CNS infections: Adjust based on pathogen and severity 1

Syphilis

• Benzathine penicillin G for early syphilis: 2.4 million units IM single dose maintains therapeutic levels (>18 ng/mL) for 18-25 days 6
• Neurosyphilis: 18-24 million units/day IV divided every 4 hours for 10-14 days 2

Pediatric Dosing

Weight-based dosing should not exceed adult maximum doses even when calculations suggest higher amounts. 7

• Arthritis: 100,000 units/kg/day in 4 divided doses for 7-10 days 1
• Meningitis: 250,000 units/kg/day in equal doses every 4 hours for 10-14 days 1
• Endocarditis: 250,000 units/kg/day in equal doses every 4 hours for 4 weeks 1
• Congenital syphilis (after newborn period): 200,000-300,000 units/kg/day (50,000 units/kg every 4-6 hours) for 10-14 days 1

Renal Dosing Adjustments

Penicillin G is relatively nontoxic, requiring dosage adjustments only in severe renal impairment. 1

• CrCl <10 mL/min/1.73m²: Full loading dose, then half the loading dose every 8-10 hours 1
• Uremic patients with CrCl >10 mL/min/1.73m²: Full loading dose, then half the loading dose every 4-5 hours 1
• Elderly patients: Reduce maintenance dose using formula: dose (million units/24h) = 4 + (creatinine clearance ÷ 7) 5

Administration Routes and Preparation

Intravenous Administration

Continuous IV infusion is preferred for high-dose therapy to maintain consistent therapeutic levels. 1, 5

• Continuous IV drip: Add appropriate daily dosage to 24-hour fluid requirement; for example, add 5 million units to each liter if patient requires 2 liters/24h with 10 million units daily dose 1
• Intermittent IV: Can be given in 4-6 divided doses 1
• Concentration: Solutions up to 100,000 units/mL can be used 1

Intramuscular Administration

IM injection is the preferred route for benzathine penicillin G, though it causes significant discomfort. 1

• Concentration: Solutions up to 100,000 units/mL minimize discomfort 1
• Benzathine penicillin G: Must be injected deep into large muscle mass 2
• Absorption: Benzathine formulation achieves median Cmax at 48 hours with mean terminal half-life of 189 hours 6

Reconstitution and Storage

Reconstituted penicillin solutions remain stable for 7 days when refrigerated. 1

• Loosen powder, hold vial horizontally, rotate while directing diluent stream against vial wall, then shake vigorously 1
• Use Sterile Water for Injection or Sterile Isotonic Sodium Chloride 1
• Critical: Penicillins are rapidly inactivated in carbohydrate solutions at alkaline pH 1

Contraindications and Precautions

Absolute Contraindications

Serious and occasionally fatal anaphylactic reactions have been reported; penicillin G is absolutely contraindicated in patients with documented IgE-mediated penicillin allergy. 1

Cross-Reactivity Warnings

Individuals with penicillin hypersensitivity history have experienced severe reactions when treated with cephalosporins. 1

• Before initiating therapy, careful inquiry must be made about previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens 1
• Cross-reactivity between penicillins and cephalosporins occurs in patients with documented penicillin allergy 1

Special Populations

Pregnancy

• Penicillin is the only acceptable treatment for syphilis in pregnancy; penicillin-allergic pregnant women must be desensitized 3
• For Group B Streptococcus prophylaxis in third trimester: 1 million units IV achieves Cmax of 67 μg/mL within 5 minutes, maintaining >12 μg/mL for 4 hours 8

Neonates

• Benzathine penicillin G should be used with extreme caution in hyperbilirubinemic neonates, especially premature infants, due to risk of bilirubin displacement and kernicterus 7

Adverse Effects

Hypersensitivity Reactions

Anaphylaxis is the most serious adverse effect, requiring immediate emergency treatment with epinephrine, oxygen, IV steroids, and airway management including intubation. 1

• Sensitivity reactions from benzathine penicillin G are less frequent and less severe than from aqueous or procaine penicillin G 9
• Reactions are more likely in individuals with penicillin hypersensitivity history and/or multiple allergen sensitivities 1

Clostridioides difficile Infection

CDAD has been reported with penicillin G use and may range from mild diarrhea to fatal colitis. 1

• CDAD must be considered in all patients presenting with diarrhea following antibiotic use 1
• CDAD has been reported to occur over 2 months after antibacterial agent administration 1
• If suspected or confirmed, discontinue ongoing antibiotic use not directed against C. difficile 1

Other Adverse Effects

• Rash, fever, diarrhea (common with cephalosporins, likely similar with penicillin) 7
• Neutropenia and liver function abnormalities (reported with cephalosporins) 7

Penicillin Allergy Management

Risk Stratification

High-risk reactions include anaphylaxis, angioedema, bronchospasm, or urticaria, suggesting IgE-mediated allergy. 4

• Determine the nature of reported penicillin allergy to stratify risk 4
• Brief antibiotic exposure does not provide adequate protection; do not assume partial treatment is sufficient 4

Skin Testing Protocol

Skin testing can be completed in 60-120 minutes with immediate results available. 2, 4

Reagents Required

• Major determinant: Benzylpenicilloyl poly-L-lysine (Pre-Pen) 6 × 10⁻⁵M 2
• Minor determinant precursors: Benzylpenicillin G (10⁻²M), benzylpenicilloate (10⁻²M), benzylpenilloate (10⁻²M) 2
• Positive control: Commercial histamine 1 mg/mL 2
• Negative control: Diluent (phenol saline) 2

Testing Procedure

1. Epicutaneous (prick) test: Duplicate drops on volar forearm, pierce epidermis with 26-gauge needle without drawing blood; positive if average wheal diameter at 15 minutes is ≥4 mm larger than negative controls 2
2. Intradermal test (if epicutaneous negative): 0.02 mL injections with 26-27 gauge needle; positive if average wheal diameter at 15 minutes is ≥2 mm larger than initial wheal and ≥2 mm larger than negative controls 2

High-Risk Patients

• Patients with anaphylaxis history, asthma, or conditions making anaphylaxis more dangerous should be tested with 100-fold dilutions before full-strength reagents 2
• Testing must occur in monitored setting with resuscitation equipment available 2, 4

Desensitization

Patients with positive skin tests require desensitization if penicillin therapy is essential (e.g., pregnant women with syphilis, endocarditis). 2, 3

• Desensitization protocols exist for both oral and IV routes 2
• Must be performed in monitored setting with immediate access to resuscitation equipment 4

Alternative Therapies

For Penicillin-Allergic Patients

Syphilis

• Early syphilis (non-pregnant): Doxycycline 100 mg PO twice daily for 14 days OR tetracycline 500 mg PO four times daily for 14 days 3, 4
• Neurosyphilis alternative: Ceftriaxone 2g daily IM or IV for 10-14 days (optimal dose/duration not well-defined) 3
• Pregnant patients: Must be desensitized and treated with penicillin; no acceptable alternatives 3

Streptococcal Infections

• Endocarditis (highly susceptible streptococci): Vancomycin 30 mg/kg/24h IV in 2 divided doses (max 2g/24h unless serum levels inappropriately low) for 4 weeks; adjust to achieve peak 30-45 μg/mL and trough 10-15 μg/mL 2
• Group A streptococcal pharyngitis: Cephalexin 500 mg twice daily for 10 days OR clindamycin 300 mg three times daily for 10 days 4

Pneumonia

• Community-acquired pneumonia: Macrolides (erythromycin) or tetracyclines for atypical pathogens (Mycoplasma pneumoniae, Chlamydia pneumoniae) 2
• Legionella infections: Erythromycin is the drug of choice 2

When Penicillin G Is Not First-Line

Penicillin G is not the drug of choice for gram-negative bacillary infections (Enterobacteriaceae). 1

• For nosocomial pneumonias: Extended-spectrum penicillin or cephalosporin plus aminoglycoside 2
• For Pseudomonas infections: Combination therapy with suitable cephalosporin or penicillin plus aminoglycoside 2
• For methicillin-sensitive S. aureus pneumonia: Semisynthetic penicillinase-resistant penicillin 2

Critical Clinical Pitfalls

Duration of Therapy

For Group A β-hemolytic streptococcal infections, maintain therapy for at least 10 days to reduce rheumatic fever risk, even if patient becomes asymptomatic earlier. 1

• Most acute infections require treatment for 48-72 hours after patient becomes asymptomatic 1
• Pneumococcal pneumonia cure probability ranges from 95% in uncomplicated infection to 50-80% with bacteremic disease 2

Resistance Considerations

Regional differences in resistance patterns exist: appreciably higher resistance to penicillin G among S. pneumoniae strains in South Africa and to erythromycin in Spain than in North America. 2

• Local antimicrobial susceptibility patterns must guide empiric therapy choices 2
• For penicillin-resistant pneumococci (MIC >0.5 mg/L), alternative regimens or combination therapy required 2

Monitoring Requirements

Gentamicin trough levels should be <0.1 mg/L when used in combination regimens to avoid renal or ototoxic effects. 2

• Determination of antimicrobial concentrations in serum is not routinely done for penicillin G 2
• Monitor patients for at least 30 minutes after initiating penicillin infusion to detect allergic reactions 4

Drug Interactions and Incompatibilities

Penicillins are rapidly inactivated in carbohydrate solutions at alkaline pH; never mix with dextrose-containing solutions. 1

• Coumarin therapy should be discontinued and replaced with heparin immediately after IE diagnosis is established 2