Penicillins

Definition and Classification
Penicillins are a major subclass of beta-lactam antibiotics, originally derived from Penicillium fungi, and represent one of the most historically important and widely used classes of antimicrobial agents. They work by inhibiting bacterial cell wall synthesis, leading to bacterial cell lysis and death. As bactericidal agents, penicillins are effective against many Gram-positive organisms, some Gram-negative organisms, and anaerobes, depending on the specific subclass.

Penicillins are divided into several groups based on their antimicrobial spectrum and resistance to beta-lactamases:

1. Natural Penicillins

2. Aminopenicillins

3. Penicillinase-resistant (anti-staphylococcal) penicillins

4. Extended-spectrum (anti-pseudomonal) penicillins

5. Penicillins combined with beta-lactamase inhibitors (covered in a previous entry)

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1. Mechanism of Action

Penicillins inhibit the final stage of bacterial peptidoglycan synthesis by binding irreversibly to penicillin-binding proteins (PBPs) on the bacterial cell wall. This disrupts cross-linking of the peptidoglycan chains, leading to weakening of the wall, osmotic instability, and cell death. Their action is time-dependent and requires active bacterial growth.

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2. Classification of Penicillins and Their Properties

Group	Examples	Spectrum	Notable Characteristics
Natural Penicillins	Penicillin G, Penicillin V	Narrow; mainly Gram-positive cocci and anaerobes	Susceptible to beta-lactamases
Aminopenicillins	Amoxicillin, Ampicillin	Extended Gram-negative activity	Still beta-lactamase susceptible
Penicillinase-resistant Penicillins	Cloxacillin, Dicloxacillin, Flucloxacillin, Nafcillin	Narrow; MSSA and Streptococcus spp.	Stable against staphylococcal beta-lactamase
Extended-spectrum Penicillins	Piperacillin, Ticarcillin	Broad spectrum, including Pseudomonas spp.	Usually paired with beta-lactamase inhibitors in clinical use

3. Natural Penicillins

a. Penicillin G (Benzylpenicillin)

• Route: IV/IM

• Acid-labile, not suitable for oral use

• Indications: Syphilis, meningitis (caused by Neisseria meningitidis), streptococcal pharyngitis, diphtheria, actinomycosis

b. Penicillin V (Phenoxymethylpenicillin)

• Route: Oral

• Acid-stable

• Indications: Streptococcal pharyngitis, mild skin infections, dental infections

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4. Aminopenicillins

a. Amoxicillin

• Route: Oral

• Better oral bioavailability than ampicillin

• Indications: Otitis media, sinusitis, bronchitis, dental abscess, Helicobacter pylori eradication (with clarithromycin and PPI)

b. Ampicillin

• Route: Oral, IV

• Broader use in hospital settings

• Indications: Listeria monocytogenes infections (e.g., meningitis), enterococcal infections, respiratory tract infections

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5. Penicillinase-Resistant Penicillins (Anti-Staphylococcal Penicillins)

Designed to resist inactivation by staphylococcal beta-lactamases.

Examples:

• Cloxacillin (oral, IM/IV)

• Dicloxacillin (oral)

• Flucloxacillin (oral, IV)

• Nafcillin, Oxacillin (IV)

Indications:

• Skin and soft tissue infections (SSTIs) due to MSSA

• Osteomyelitis

• Septic arthritis

• Endocarditis

These drugs do not cover MRSA (methicillin-resistant Staphylococcus aureus).

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6. Extended-Spectrum Penicillins

Primarily used in hospital settings due to broader Gram-negative activity, including Pseudomonas aeruginosa.

a. Piperacillin

• Usually combined with tazobactam (see beta-lactamase inhibitor combinations)

• IV use only

b. Ticarcillin

• Rarely used alone

• Combined with clavulanic acid (Timentin – now discontinued in many markets)

Indications:

• Severe hospital-acquired infections

• Intra-abdominal infections

• Febrile neutropenia

• Complicated UTIs and SSTIs

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7. Pharmacokinetics

Property	Details
Absorption	Varies by drug; amoxicillin is well absorbed orally; penicillin G is IV only
Distribution	Good tissue penetration; limited CNS penetration unless meninges are inflamed
Protein binding	Moderate to high
Metabolism	Minimal hepatic metabolism
Excretion	Primarily renal (glomerular filtration and tubular secretion)
Half-life	Short (generally < 2 hours)

Dose adjustment is required in renal impairment for most penicillins, especially IV forms.

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8. Dosage Examples

Drug	Typical Adult Dose	Route
Penicillin V	250–500 mg every 6–8 hours	Oral
Amoxicillin	500–875 mg every 8–12 hours	Oral
Ampicillin	1–2 g every 4–6 hours	IV
Flucloxacillin	250–500 mg every 6 hours	Oral or IV
Piperacillin (alone)	3–4 g every 6–8 hours (rare as monotherapy)	IV

9. Adverse Effects

System Affected	Common Adverse Effects
Gastrointestinal	Nausea, vomiting, diarrhea (esp. amoxicillin)
Hypersensitivity reactions	Urticaria, angioedema, anaphylaxis
Hematologic	Neutropenia, thrombocytopenia (rare, usually with prolonged use)
Hepatic	Cholestatic hepatitis (esp. with flucloxacillin)
CNS (high doses or renal impairment)	Seizures, encephalopathy
Renal	Interstitial nephritis (rare)

10. Contraindications and Cautions

Contraindication	Explanation
Severe allergy to penicillins	Cross-reactivity with other beta-lactams possible
Previous cholestatic jaundice (amoxicillin-clavulanate)	Avoid re-exposure
Renal impairment	Dose adjustment required to avoid accumulation

11. Drug Interactions

Drug/Class	Interaction
Methotrexate	Reduced excretion; increased methotrexate toxicity
Allopurinol	Increased risk of rash (especially with ampicillin)
Oral contraceptives	May reduce efficacy (altered gut flora)
Probenecid	Inhibits renal excretion, increasing serum penicillin levels
Aminoglycosides (IV)	Can be synergistic against some bacteria

12. Resistance Mechanisms

Mechanism	Details
Beta-lactamase production	Common in Gram-negative and Staphylococcus aureus
PBP alterations	MRSA produces PBP2a; Streptococcus pneumoniae may alter PBP structure
Efflux pumps	Found in some Gram-negative organisms
Porin loss	Decreased permeability in Gram-negative outer membranes

13. Clinical Use by Infection Type

Infection	Preferred Penicillin
Strep throat	Penicillin V
Otitis media, sinusitis	Amoxicillin
Syphilis	Penicillin G (IM or IV)
MSSA skin infection	Flucloxacillin, Cloxacillin
Dental abscess	Amoxicillin, Phenoxymethylpenicillin
Listeria meningitis	Ampicillin
Endocarditis (Strep viridans)	Penicillin G
Animal bite	Amoxicillin-clavulanate

14. Special Populations

Group	Recommendation
Pregnancy	Generally safe; Category B
Children	Widely used; amoxicillin is first-line for many infections
Renal impairment	Adjust dose to prevent toxicity
Hepatic disease	Monitor LFTs if using flucloxacillin

15. Advantages of Penicillins

• Highly effective against many Gram-positive pathogens

• Low toxicity profile

• Multiple oral and parenteral options

• Well-studied safety in pregnancy and pediatrics

• Broad clinical experience and guidelines supporting use

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16. Limitations

• Widespread resistance limits monotherapy in many infections

• Allergic reactions limit use in some patients

• Short half-life requires frequent dosing

• Beta-lactamase susceptibility necessitates combination therapy in many cases

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17. Notable Penicillin Derivatives (Beyond Traditional Forms)

Drug	Formulation	Notes
Benzathine penicillin G	Long-acting IM injection	Used for syphilis (single-dose treatment)
Procaine penicillin G	Intermediate-acting IM injection	Formerly used in streptococcal infections