Natural penicillins

I. Introduction

Natural penicillins are a subgroup of the β-lactam antibiotic class derived from the original penicillin molecule discovered by Alexander Fleming in 1928. They represent the earliest generation of penicillin antibiotics and are still relevant in clinical practice today due to their potent activity against gram-positive cocci, gram-positive bacilli, and some gram-negative cocci. These agents function by inhibiting bacterial cell wall synthesis, making them bactericidal.

Natural penicillins remain first-line agents for infections caused by Streptococcus spp., Treponema pallidum (syphilis), Clostridium spp., and Neisseria meningitidis, provided the strain is susceptible.

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II. Core Structure and Mechanism of Action

All natural penicillins contain the β-lactam ring fused with a thiazolidine ring, which is essential for antibacterial activity.

Mechanism:

1. Penicillins bind to penicillin-binding proteins (PBPs), which are transpeptidase enzymes involved in the cross-linking of peptidoglycan in the bacterial cell wall.

2. Inhibition of PBPs results in:

   • Disruption of cell wall synthesis

   • Weakened peptidoglycan structure

   • Cell lysis and death due to osmotic instability

These agents are time-dependent bactericidal antibiotics, meaning their efficacy correlates with the time the drug concentration remains above the MIC (Minimum Inhibitory Concentration).

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III. Classification of Natural Penicillins

The natural penicillins include:

1. Penicillin G (Benzylpenicillin)

2. Penicillin V (Phenoxymethylpenicillin)

3. Repository forms of Penicillin G:

   • Procaine Penicillin G

   • Benzathine Penicillin G

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IV. Pharmacological Profiles

1. Penicillin G (Benzylpenicillin)

• Route: Intravenous (IV) or Intramuscular (IM)

• Spectrum:

  • Gram-positive cocci (Streptococcus pyogenes, S. pneumoniae)

  • Gram-positive bacilli (Clostridium spp., Actinomyces)

  • Gram-negative cocci (Neisseria meningitidis)

  • Anaerobes (mouth flora)

  • Spirochetes (Treponema pallidum)

• Limitations: Not stable in stomach acid → not orally available

• Elimination: Renal (dose adjust in renal impairment)

• Half-life: Short (~30 minutes), necessitating frequent dosing unless extended with procaine or benzathine

2. Penicillin V (Phenoxymethylpenicillin)

• Route: Oral

• Acid-stable: Can survive stomach acid; better for outpatient therapy

• Uses:

  • Streptococcal pharyngitis

  • Minor skin infections

• Limitations: Narrow spectrum; not suitable for severe systemic infections

3. Benzathine Penicillin G

• Route: Intramuscular

• Formulation: Slow absorption → prolonged low serum levels

• Half-life: Long-acting (up to 2–4 weeks)

• Uses:

  • Syphilis (early and latent stages)

  • Rheumatic fever prophylaxis (monthly injections)

  • Streptococcal pharyngitis (in non-compliant patients)

4. Procaine Penicillin G

• Route: Intramuscular

• Half-life: Intermediate-acting (daily dosing)

• Uses:

  • Streptococcal soft tissue infections

  • Pneumococcal infections

• Limitations: Superseded by more convenient agents

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V. Antibacterial Spectrum

Natural penicillins are primarily effective against non-β-lactamase-producing organisms:

Gram-Positive Aerobes:

• Streptococcus pyogenes

• Streptococcus pneumoniae (some resistance)

• Enterococcus faecalis (variable susceptibility)

Gram-Positive Anaerobes:

• Clostridium perfringens

• Actinomyces israelii

Gram-Negative Cocci:

• Neisseria meningitidis

Spirochetes:

• Treponema pallidum (syphilis)

• Leptospira interrogans

Oral Anaerobes:

• Peptostreptococcus spp.

• Fusobacterium spp.

Not Active Against:

• Staphylococcus aureus (due to β-lactamase production)

• Gram-negative bacilli

• Pseudomonas

• Enterobacteriaceae

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VI. Clinical Uses

1. Streptococcal Infections

• Pharyngitis

• Scarlet fever

• Cellulitis

• Rheumatic fever prophylaxis (benzathine penicillin)

2. Syphilis and Other Spirochetal Infections

• Benzathine penicillin G remains the gold standard for syphilis treatment

• Also effective in yaws and bejel (non-venereal treponematoses)

3. Meningococcal Infections

• Meningitis and bacteremia caused by N. meningitidis

4. Clostridial Infections

• C. perfringens (gas gangrene)

• C. tetani (adjunctive therapy)

5. Actinomycosis

• Actinomyces israelii infection

6. Diphtheria (as adjunct)

• Alongside antitoxin

7. Leptospirosis

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VII. Resistance Mechanisms

1. β-lactamase (penicillinase) production:

   • Common in Staphylococcus aureus

   • Breaks open β-lactam ring → inactivates drug

2. Altered PBPs:

   • Especially in penicillin-resistant Streptococcus pneumoniae

3. Reduced permeability or increased efflux:

   • Less relevant to natural penicillins due to narrow spectrum

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VIII. Adverse Effects

1. Hypersensitivity Reactions (most significant)

   • Rash

   • Urticaria

   • Angioedema

   • Anaphylaxis (rare but life-threatening)

   • Cross-reactivity with other β-lactams (~5–10%)

2. Gastrointestinal

   • Nausea, diarrhea (more with oral penicillin V)

3. Neurotoxicity

   • High doses → seizures (especially in renal failure)

4. Hematologic

   • Eosinophilia

   • Coombs-positive hemolytic anemia (rare)

5. Jarisch-Herxheimer Reaction

   • Transient febrile reaction in syphilis treatment (due to spirochete lysis)

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IX. Contraindications

• History of serious hypersensitivity to penicillins or β-lactams

• Use with caution in renal insufficiency (dose adjustment required for Penicillin G)

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X. Drug Interactions

Interacting Drug	Interaction Description
Probenecid	↓ Renal tubular secretion → ↑ penicillin levels
Oral contraceptives	↓ Efficacy (controversial but precautionary)
Methotrexate	Penicillin may ↓ clearance → ↑ toxicity risk
Tetracyclines	Antagonistic effect (inhibit bacteriostatic effect of penicillin)

XI. Dosing and Administration

Drug	Route	Adult Dose	Frequency
Penicillin G (IV)	IV	2–4 million units every 4–6h	Severe infections
Penicillin V	Oral	250–500 mg every 6–8h	Pharyngitis, dental
Benzathine Penicillin G	IM	1.2–2.4 million units once	Syphilis, prophylaxis
Procaine Penicillin G	IM	600,000–1.2 million units/day	Soft tissue infections

XII. Comparison with Other Penicillins

Category	Examples	Spectrum
Natural Penicillins	Penicillin G, V	Gram-positive cocci, spirochetes
Penicillinase-resistant	Oxacillin, Dicloxacillin	S. aureus (non-MRSA)
Aminopenicillins	Amoxicillin, Ampicillin	Broader gram-negative, still β-lactamase sensitive
Extended-spectrum	Piperacillin, Ticarcillin	Pseudomonas and more gram-negatives
β-lactam + inhibitor	Amoxicillin-clavulanate	β-lactamase-producing organisms

XIII. Role in Antimicrobial Stewardship

• Natural penicillins are narrow-spectrum and microbiologically targeted

• They are preferred when organism is known to be highly susceptible

• Promote responsible use by limiting unnecessary broad-spectrum exposure

• Help reduce resistance pressure and preserve flora

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XIV. Use in Special Populations

Population	Considerations
Pregnancy	Generally safe (Category B)
Pediatrics	Widely used; weight-based dosing
Renal impairment	Dose adjustment required for IV forms
Elderly	Monitor renal function and dosing closely