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Beta-Lactam Antibiotics

What Makes a Drug a "Beta-Lactam"?

• Penicillins
• Cephalosporins
• Monobactams
• Carbapenems
• Beta-lactamase inhibitors

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1. Mechanism of Action

1. Bacteria build their cell wall from peptidoglycan - alternating N-acetylglucosamine (G) and N-acetylmuramic acid (M) strands cross-linked by peptide chains.
2. This cross-linking is done by an enzyme called transpeptidase (also called Penicillin-Binding Protein / PBP).
3. Beta-lactams bind irreversibly to PBPs and block transpeptidation, so the cell wall cannot form properly.
4. The bacterium cannot maintain osmotic integrity and lyses (dies).

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2. Penicillins

Classification of Penicillins

Pharmacokinetics

• Penicillin G is acid-labile - must be given IV/IM
• Penicillin V, amoxicillin - acid-stable, given orally
• Excreted via the kidneys (dose-adjust in renal failure)
• Poor CNS penetration unless meninges inflamed

Clinical Uses

• Penicillin G: Streptococcal infections, syphilis, meningococcal meningitis
• Amoxicillin: Otitis media, sinusitis, H. pylori (with clarithromycin)
• Piperacillin-tazobactam: Hospital-acquired infections, Pseudomonas

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3. Cephalosporins

Generations at a Glance

Key Points

• Ceftriaxone (half-life 7-8 hours): Once daily dosing; drug of choice for gonococcal infections and meningitis; biliary excretion (no renal dose adjustment needed)
• Ceftazidime: Only 3rd-gen with Pseudomonas coverage
• Ceftaroline: Only cephalosporin active against MRSA
• Cephalosporins are NOT active against Listeria monocytogenes or Enterococci (except ceftaroline with some enterococcal activity)

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4. Carbapenems

• Broadest spectrum of all antibiotics
• Active against gram-positives, gram-negatives, and anaerobes
• Imipenem is given with cilastatin (inhibits renal dehydropeptidase that degrades imipenem)
• Meropenem/Doripenem: Stable to renal dehydropeptidase, given alone
• Drug of choice for ESBL-producing organisms
• NOT active against MRSA, Stenotrophomonas

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5. Monobactams

• Active only against gram-negative aerobes (including Pseudomonas)
• No activity against gram-positives or anaerobes
• Safe in penicillin-allergic patients (no cross-reactivity except with ceftazidime)
• Useful in gram-negative infections in patients with beta-lactam allergy

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6. Beta-Lactamase Inhibitors

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7. Resistance Mechanisms

1. Beta-lactamase production (most common) - enzymes that hydrolyze the beta-lactam ring (e.g., ESBL, AmpC, carbapenemases like KPC, NDM)
2. Modified PBPs - altered target with reduced affinity (e.g., MRSA has PBP2a encoded by mecA gene)
3. Impaired drug penetration - loss of outer membrane porins in gram-negatives
4. Efflux pumps - active expulsion of the drug

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8. Adverse Effects

• Hypersensitivity/Allergy (most important): Ranges from maculopapular rash to anaphylaxis. IgE-mediated anaphylaxis is most dangerous. Cross-reactivity between penicillins and cephalosporins is low (~1-2%).
• GI disturbance: Diarrhea, nausea, C. difficile colitis (especially with broad-spectrum agents)
• Seizures: At high doses (especially imipenem and penicillin G in CNS)
• Nephrotoxicity: Methicillin (no longer used) caused interstitial nephritis
• Ceftriaxone: Can cause biliary sludge/pseudolithiasis, especially in children; avoid in neonates with hyperbilirubinemia (displaces bilirubin from albumin)

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Summary Table

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Penicillin - Complete Pharmacology

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1. HISTORY

• 1928 - Alexander Fleming, at St. Mary's Hospital London, observed that a mold (Penicillium notatum) contaminating a Staphylococcus culture caused bacterial lysis. He named the substance penicillin.
• 1940 - Howard Florey, Ernst Chain, and Abraham at Oxford purified it and showed dramatic therapeutic effect in mice with streptococcal infections.
• 1941 - First human trial: a policeman with severe mixed staph/strep infection was treated with penicillin - some recovered from the urine of other patients (hence the famous quote: "purified by passage through the Oxford Police Force").
• 1942 - 122 million units produced in the US; first clinical trials at Yale and Mayo Clinic.
• 1943 - Adopted by US Armed Forces; deep-fermentation procedure enabled mass production.
• By 1950: over 200 trillion units (nearly 150 tons) produced per year.

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2. SENSITIVE (HISTORY-POSITIVE) ORGANISMS

Gram-Positive Cocci

Gram-Positive Rods

Gram-Negative Cocci

Spirochetes

Gram-Negative Anaerobes

• Most susceptible except Bacteroides fragilis (resistant - produces cephalosporinase)

NOT Sensitive to Penicillin

• MRSA, most Staphylococcus aureus (>90% resistant via beta-lactamase)
• Most gram-negative enteric bacilli (E. coli, Klebsiella, Pseudomonas)
• Amebae, fungi, viruses, Rickettsiae, Mycoplasma

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3. CHEMISTRY

Core Structure (6-Aminopenicillanic Acid)

• Ring A = Thiazolidine ring (5-membered, contains sulfur)
• Ring B = Beta-lactam ring (4-membered - the defining feature)
• R group = Side chain at the secondary amino group (RNH-); determines spectrum, stability, and route
• 6-aminopenicillanic acid nucleus = Rings A + B together - structural integrity is essential for activity
• Beta-lactamase opens the beta-lactam ring → yields penicilloic acid (inactive)

Key Points

• Carbapenems have a different stereochemical configuration in the lactam ring - this imparts resistance to most common beta-lactamases
• Monobactams have only the beta-lactam ring (no fused ring)

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4. CLASSIFICATION

A. Natural Penicillins

B. Antistaphylococcal (Penicillinase-Resistant) Penicillins

C. Aminopenicillins (Extended Spectrum)

D. Antipseudomonal Penicillins

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5. PHARMACOKINETICS

Absorption

Distribution

• Widely distributed to joint fluid, pleural, pericardial fluid, bile
• Poor CNS penetration normally (<1% of plasma); increases to ~5% with meningeal inflammation
• Poor intracellular penetration (polar molecules - stay extracellular)
• Poor penetration: prostatic secretions, intraocular fluid, brain parenchyma

Metabolism & Excretion

• Eliminated rapidly via glomerular filtration + renal tubular secretion
• Half-life = 30-90 minutes (short)
• Probenecid (blocks tubular secretion) - delays excretion and prolongs action
• Dose adjustment needed in renal failure (except nafcillin - hepatic excretion)
• Anuria extends t1/2 of Pen G from 0.5 h to ~10 h
• Urine concentrations are very high (useful for urinary tract infections)

Long-acting Preparations

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6. PHARMACODYNAMICS

Mechanism of Action (Bactericidal)

1. Bacteria build cell walls from peptidoglycan (alternating N-acetylglucosamine and N-acetylmuramic acid chains cross-linked by peptide bridges)
2. Cross-linking is performed by transpeptidase enzyme located at Penicillin-Binding Proteins (PBPs)
3. Penicillin binds irreversibly to PBPs and inhibits transpeptidation → peptidoglycan synthesis halts
4. Cell wall weakens → bacterium lyses from osmotic pressure

Resistance Mechanisms

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7. INDICATIONS & CLINICAL USES

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8. CONTRAINDICATIONS

• Use cautiously in history of asthma, hives, or atopy
• Mild penicillin rash (non-IgE) is NOT a contraindication to cephalosporins

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9. ADVERSE EFFECTS

Hypersensitivity (Most Common & Important)

• Anaphylaxis incidence: 0.004-0.04%; fatal anaphylaxis: 0.001%
• Penicillin acts as a hapten - penicilloyl moiety (major determinant) binds to proteins to trigger immune response
• Ampicillin rash: ~9% incidence; nearly 100% in patients with EBV (mono)

Other Adverse Effects

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10. DOSES & ROUTES

Penicillin G

Penicillin V

Ampicillin

Amoxicillin

Nafcillin / Oxacillin (IV)

Dicloxacillin (Oral)

Piperacillin-Tazobactam

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Memory Tip for Penicillin-Sensitive Organisms: "SPACE MLS"

• Streptococci (most) | Pneumococci (sensitive strains) | Actinomyces | Clostridium | Enterococci (ampicillin)
• Meningococci | Listeria (ampicillin) | Spirochetes (Treponema, Borrelia, Leptospira)