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Penicillins

1. Chemistry and Structure

• Amidase cleaves the side-chain amide bond (removing the R group)
• Penicillinase (beta-lactamase) cleaves the beta-lactam ring C-N bond, inactivating the drug
• Jawetz, Melnick & Adelberg's Medical Microbiology 28th Ed.
• Goodman & Gilman's Pharmacological Basis of Therapeutics

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2. Mechanism of Action

• Cell wall synthesis stops
• Existing walls weaken under osmotic stress
• Autolytic enzymes (murein hydrolases) are activated
• Bactericidal lysis occurs (both lytic and non-lytic mechanisms contribute)

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3. Classification and Spectrum

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4. Pharmacokinetics

• Distribution: Widely distributed; achieves therapeutic levels in joint fluid, pleural fluid, pericardial fluid, bile
• Poor penetration: Prostate secretions, brain tissue, intraocular fluid, intracellular (phagocytes)
• CSF: <1% of plasma when meninges normal; up to 5% with meningeal inflammation - adequate for treating meningitis at high IV doses
• Elimination: Primarily by renal tubular secretion + glomerular filtration; half-lives typically 30-90 min; high urinary concentrations
• Probenecid blocks renal tubular secretion, raising and prolonging penicillin blood levels
• Food: Most oral penicillins should be taken 1-2 hours before or after meals (amoxicillin is the exception - can be taken with food)
• Dose adjustment: Required in renal failure (high-dose pen G can cause seizures in renal failure)

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5. Clinical Uses by Agent

Penicillin G (IV)

• Streptococcal infections (4-24 million units/day IV in 4-6 divided doses or continuous infusion)
• Meningococcal meningitis
• Neurosyphilis
• Actinomycosis
• Clostridial infections
• Some enterococcal infections (synergy with aminoglycosides)

Penicillin V (oral)

• Minor streptococcal infections only
• Poor bioavailability; narrow spectrum; amoxicillin often preferred

Benzathine Penicillin G (IM depot)

• Single dose 1.2 million units IM: treats beta-hemolytic strep pharyngitis
• 1.2 million units IM every 3-4 weeks: rheumatic fever prophylaxis
• 2.4 million units IM weekly x 1-3 weeks: syphilis treatment

Procaine Penicillin G

• Intermediate-acting IM depot; largely replaced by newer agents

Oxacillin / Nafcillin (IV)

• MSSA serious infections (endocarditis, bacteremia): 8-12 g/day IV
• Drug of choice for methicillin-susceptible staphylococci

Dicloxacillin / Cloxacillin (oral)

• Mild-moderate MSSA infections (skin/soft tissue): 0.25-0.5 g PO q4-6h

Ampicillin (IV/oral)

• Enterococcal infections, Listeria meningitis, susceptible gram-negatives
• 4-12 g/day IV for serious infections

Amoxicillin (oral)

• Otitis media, sinusitis, community-acquired pneumonia (strep), H. pylori (triple therapy)
• 250-500 mg TID

Amoxicillin-clavulanate / Ampicillin-sulbactam / Piperacillin-tazobactam

• Beta-lactamase inhibitor combinations that restore activity against many beta-lactamase-producing organisms

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6. Mechanisms of Resistance

(a) Beta-lactamase Production (most common)

• Enzymes that hydrolyze the beta-lactam ring
• Gram-positives (e.g., S. aureus): secrete large amounts of narrow-spectrum penicillinase; gene carried on plasmid, transferable by bacteriophage, expression inducible
• Gram-negatives: produce beta-lactamases in smaller amounts but strategically located in the periplasmic space - maximally protecting the cell
• ESBL (extended-spectrum beta-lactamases): hydrolyze most penicillins AND cephalosporins
• Carbapenemases (e.g., KPC): hydrolyze nearly all beta-lactams

(b) Altered Penicillin-Binding Proteins

• PBPs acquire mutations reducing beta-lactam affinity
• Key example: MRSA expresses PBP2a (encoded by mecA gene) - very low affinity for all beta-lactams
• Penicillin-resistant pneumococci: altered PBPs

(c) Reduced Permeability / Efflux Pumps

• Gram-negatives reduce outer membrane porin channels (e.g., OprD loss in Pseudomonas)
• Active efflux pumps remove drug before it can act

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7. Adverse Effects

• ~5-8% of patients report penicillin allergy, but only a small fraction have true IgE-mediated allergy
• Penicillin skin testing can evaluate type I (immediate) hypersensitivity
• Negative skin test = most patients can safely receive penicillin
• If penicillin is essential (e.g., enterococcal endocarditis, neurosyphilis in a penicillin-allergic patient): desensitization with gradually increasing doses is possible
• Cross-reactivity with cephalosporins is real but low (~1-2% in patients with penicillin allergy)

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8. Beta-Lactamase Inhibitors

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Summary: Spectrum at a Glance

Narrow (Pen G/V)        → Gram-positives, spirochetes, some anaerobes
Anti-staph (oxacillin)  → MSSA only
Aminopenicillins        → Above + limited gram-negatives (but no Pseudomonas)
Pip-tazo                → Broad spectrum incl. Pseudomonas

Sources: Katzung's Basic and Clinical Pharmacology 16th Ed. | Goodman & Gilman's Pharmacological Basis of Therapeutics | Jawetz, Melnick & Adelberg's Medical Microbiology 28th Ed.

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Penicillins - MUHS 2nd Year B.P.Th. Pharmacology

Exam Pattern (as per MUHS analysis): Classification | Mechanism of Action | Clinical Indications | ADRs This topic appears in Winter & Winter exam cycles - expect 10-mark long answers or 5-mark short notes.

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CLASSIFICATION OF PENICILLINS

Group 1 - Natural Penicillins

Group 2 - Beta-Lactamase Resistant (Anti-Staphylococcal) Penicillins

Group 3 - Aminopenicillins (Extended Spectrum)

Group 4 - Antipseudomonal Penicillins (Ureidopenicillins)

Memory tip: N-A-C-D for anti-staph penicillins: Nafcillin, Ampicillin (no - that's amino), actually: Nafcillin, Oxacillin, Cloxacillin, Dicloxacillin = NOCD

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MECHANISM OF ACTION

Basic Concept

Step-by-Step Mechanism

• Bacterial cell wall is made of peptidoglycan - a mesh of NAG (N-acetylglucosamine) and NAM (N-acetylmuramic acid) strands cross-linked by short peptide bridges
• The final cross-linking step is done by an enzyme called transpeptidase (also called Penicillin-Binding Protein / PBP)

• Penicillin structurally mimics D-Ala-D-Ala, the terminal end of the peptide precursor
• It binds irreversibly to PBPs (transpeptidase) and blocks cross-linking
• Without cross-linking, the cell wall becomes structurally weak

• Weak cell wall cannot withstand osmotic pressure
• Bacterial autolytic enzymes (murein hydrolases) are activated
• Cell undergoes lysis and death

Important Pharmacodynamic Point

Mechanism of Resistance (MUHS may ask this as part of MOA)

1. Beta-lactamase production (most common)
   • Bacteria produce enzymes that break open the beta-lactam ring
   • Example: MRSA, beta-lactamase-producing H. influenzae
   • Overcome by: combining with beta-lactamase inhibitors (clavulanate, sulbactam, tazobactam)
2. Altered PBPs
   • PBPs mutate to have low affinity for penicillin
   • Key example: MRSA produces PBP2a (encoded by mecA gene) - resistant to ALL beta-lactams
3. Reduced permeability / Efflux pumps
   • Gram-negative bacteria reduce porin channels, limiting drug entry
   • Efflux pumps actively expel the drug

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CLINICAL INDICATIONS (Uses)

Penicillin G and V (Natural Penicillins)

Antistaphylococcal Penicillins (Oxacillin, Nafcillin, Cloxacillin, Dicloxacillin)

• Skin and soft tissue infections caused by MSSA (Methicillin-Susceptible S. aureus)
• Staphylococcal endocarditis (oxacillin/nafcillin IV)
• Staphylococcal osteomyelitis
• NOT used for MRSA (vancomycin is used for MRSA)

Aminopenicillins (Ampicillin, Amoxicillin)

Piperacillin-Tazobactam (Pip-Tazo)

• Hospital-acquired infections
• Ventilator-associated pneumonia
• Intra-abdominal infections (anaerobes + gram-negatives)
• Pseudomonal infections
• Febrile neutropenia (empiric)

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ADVERSE DRUG REACTIONS (ADRs)

1. Hypersensitivity Reactions (Most Important)

• Anaphylaxis incidence = very rare (0.05% of recipients) - but potentially fatal
• ~5-8% of patients claim penicillin allergy, but most do NOT have true allergy
• Penicillin skin test is used to evaluate Type I hypersensitivity before giving the drug
• If allergic but penicillin essential (e.g., neurosyphilis): perform desensitization with gradually increasing doses
• Cross-reactivity with cephalosporins - exists but is low (~1-2%)

2. Ampicillin / Amoxicillin - Specific Rash

• Non-immune maculopapular skin rash
• Notably seen in Epstein-Barr virus (EBV) / Infectious Mononucleosis - avoid ampicillin/amoxicillin in these patients
• Also seen in CLL patients and with allopurinol co-administration

3. CNS Toxicity

• Seizures with high-dose Penicillin G in patients with renal failure (due to drug accumulation)
• Mechanism: GABA receptor antagonism at very high drug levels

4. Organ-Specific Toxicities

5. GI Effects

• Nausea, vomiting, diarrhea (especially with large oral doses)
• Clostridium difficile (C. diff) pseudomembranous colitis - associated with broad-spectrum penicillins disrupting gut flora

6. Superinfections

• Secondary oral candidiasis (thrush)
• Vaginal candidiasis
• Due to disruption of normal microbial flora

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SEMI-SYNTHETIC PENICILLINS - Key Points (MUHS specifically asks this)

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QUICK REVISION TABLE - MUHS Exam Ready

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EXAM TIPS FOR MUHS BPTh

1. Long answer (10 marks): Write Classification + MOA + Clinical Uses + ADRs with headings. Draw the beta-lactam ring and label where penicillinase acts.
2. Short note (5 marks): Focus on MOA alone - explain PBP inhibition in steps, or write ADRs with hypersensitivity types clearly tabulated.
3. Always mention: Time-dependent killing, bactericidal nature, and that they do NOT cover MRSA (except ceftaroline among cephalosporins, but not penicillins).
4. Clinical correlation for physiotherapy context: Penicillins may be given to BPTh patients with post-surgical wound infections, cellulitis, or pneumonia - know their ADRs to counsel patients about rash, GI upset, and allergic warning signs.

Sources: Katzung's Basic and Clinical Pharmacology 16th Ed. | Goodman & Gilman's Pharmacological Basis of Therapeutics | Jawetz, Melnick & Adelberg's Medical Microbiology 28th Ed.