Beta-Lactam Antibiotics Overview

Beta-Lactam Antibiotics

• Beta-lactam antibiotics have a beta-lactam ring as their essential antibacterial component.
• This group includes Penicillins, Cephalosporins, Carbapenems, and Monobactams.

Penicillins

• Chemistry: The penicillin nucleus contains a beta-lactam ring. The basic chemical structure is 6-aminopenicillanic acid.
• Source:
  • Natural: derived from molds (fungi), including penicillin G and Penicillin V.
  • Semisynthetic: chemically modified forms.
• Preparations of Penicillins:
  • 1. Benzyl Penicillin (Penicillin G): Short duration of action (4-6 hours), acid-sensitive, and susceptible to β-lactamases. Limited effectiveness against Gram-negative bacilli.
  • 2. Long-Acting Penicillins: Procaine penicillin G (12 hours), Fortified Procaine Penicillin G (24 hours), and Benzathine Penicillin G (monthly).
  • 3. Acid-Resistant Penicillins: Phenoxymethyl penicillin (Penicillin V).
  • 4. β-Lactamase Resistant: Methicillin (obsolete due to nephrotoxicity), primarily used for diagnosing Methicillin-resistant Staphylococcus aureus (MRSA) infections.
  • 5. Acid & β-Lactamase Resistant: Oxacillin, Cloxacillin, and nafcillin (IV for severe staph infections).
  • 6. Broad-Spectrum: Effective against Gram-positive and Gram-negative bacteria, including Salmonella, Shigella, H. influenza, and H. pylori, but not against Klebsiella, Proteus, and Pseudomonas aeruginosa. These drugs are often lactamase-sensitive and acid-resistant.
  • 6a. Ampicillin: Incomplete oral absorption, affected by food, and has a short duration of action (6 hours). Useful in enteritis, though it distrubs the gut flora.
  • 6b. Pro-drugs of ampicillin: (e.g., Pivampicillin and Bacampicillin). These are better absorbed than ampicillin itself and do not affect the gut flora.
  • 6c. Amoxicillin: Similar to ampicillin but complete oral absorption and less affected by food; also, less effect on the gut flora. Longer duration of action (8 hours).
  • 7. Antipseudomonal: Broad spectrum, effective against Pseudomonas aeruginosa and Proteus, and are β-lactamase sensitive.
  • 8. Reversed-Spectrum: Effective against Gram-negative bacteria (e.g., Salmonella & Shigella), but not Pseudomonas, Klebsiella, or H. influenza.

Pharmacokinetics of Penicillins

• Distribution: Do not pass the blood-brain barrier (BBB) readily, but can pass inflamed tissues. Pass the placental barrier, but are not teratogenic. Active renal tubular excretion, which is inhibited by Probenecid. Adjust dosage for patients with impaired renal function, except Nafcillin, which is excreted in bile.
• Metabolism: Metabolized by bacterial enzymes (penicillinase). This leads to the inactive penicilloic acid, and can cause allergic reactions.

Antibacterial Activity of Penicillins

• Mechanism of Action: Penicillins bind to penicillin-binding proteins (PBPs) inhibiting transpeptidase enzymes, which inhibits cross-linking in peptidoglycan. The bacterial cell wall synthesis is affected as a result. This leads to autolytic enzyme activation and cell wall lysis.
• Activity: Penicillins are bactericidal, mainly acting on growing bacteria.
• Resistance:
  • Natural: due to the absence of peptidoglycans (e.g., Mycoplasma).
  • Acquired: synthesis of beta-lactamases (penicillinases). Alteration in the PBP binding sites, decreased permeability, and increased efflux.

Spectrum of Penicillins

• Narrow Spectrum: Active against Gram-positive bacteria (cocci and bacilli), Gram-negative cocci, anerobes except certain bacteria like Bacteroides fragilis, spirochaetes like Treponema pallidum, and Actinomyces Israeli.
• Broad Spectrum: Active against Gram-positive and Gram-negative bacilli, but not Pseudomonas, Proteus, or Klebsiella.
• Extended Spectrum: Active against a broad range including Pseudomonas, Proteus, and Klebsiella.

Indications of Penicillins

• Chemoprophylaxis: Prevention of streptococcal infections (rheumatic fever), endocarditis, and before dental procedures in patients with valve disease or prosthetic valves.
• Treatment: Respiratory tract infections, Urinary tract infections, gastrointestinal infections (e.g., typhoid fever and eradication of H. pylori), meningitis, and gonorrhea. Pyogenic infections (e.g., abscesses, osteomyelitis), endocarditis, diphtheria, tetanus, gas gangrene, anthrax, actinomycosis, and syphilis.

Adverse Effects of Penicillins

• Hypersensitivity: Allergic reactions due to penicilloic acid acting as a hapten. Manifests as rash, urticaria, angioedema, or anaphylactic shock. Prevented by history and skin tests. No re-use recommended. Cross-allergy between penicillins and other beta-lactams (e.g., cephalosporins) is seen in about 10% of patients.
• "Maculopapular rash" due to Allergy, Leukemia, infectious mononucleosis, or treatment by allopurinol can also occur.
• Jarisch-Herxheimer reaction: due to release of toxins from dead Treponema in syphilitic patients, manifestations are like an allergic reaction and treated with cortisone.
• Diarrhea and superinfection: Due to Monilia (Candida) or endotoxin, from Staph. or Clostridium difficile (treated with Nystatin or other drugs).
• Seizures: From large doses, or intrathecal injection.
• Electrolyte Imbalance: Sodium (Na+) and Potassium (K+) salts used can cause hypernatremia or hyperkalemia
• Pain, Induration, and Thrombophlebitis: Local effects from IM and IV injection, respectively.
• Platelet Dysfunction: Carboxypenicillin.
• Nephrotoxicity: Methicillin and some other penicillins can cause nephrotoxicity. The dose should be adjusted in renal impairment..

Other Beta-Lactam Antibiotics

Cephalosporins

• Chemistry: similar to penicillin.
• Generations differ based on spectrum, resistance to beta-lactamases, and ability to cross the BBB.
• 1st Generation: more active on Gram-positive than Gram-negative bacteria; resistant to beta-lactamases, does not cross BBB.
• 2nd Generation: More active on Gram-negative than Gram-positive; more resistant to beta-lactamases than 1st generation; does not cross BBB except Cefuroxime.
• 3rd Generation: More active on Gram-negative bacteria than 2nd generation; More resistant to beta-lactamases; crosses BBB except Cefoperazone. Excretion and metabolism varies between drugs.
• 4th Generation: Similar to Ceftazidime, but more resistant to beta-lactamases.
• Pharmacokinetics: Active renal tubular excretion, which is inhibited by Probenecid, except for drugs that are primarily excreted through bile (e.g., Ceftriaxone).
• Spectrum: varies for each generation
• Indications: Respiratory, urinary tract, meningitis, typhoid, anaerobic, pyogenic infections, and prophylaxis.
• Adverse effects: Hypersensitivity, Diarrhea, Pain and Induration, formation of insoluble salts, disulfiram-like action, Hypoprothrombinemia, nephrotoxicity (especially with aminoglycosides or loop diuretics), and platelet dysfunction.

Carbapenems

• Members: Imipenem, Meropenem, Ertapenem.
• Source: Synthetic.
• Chemistry: Beta-lactam antibiotics.
• Pharmacokinetics: Given IV and can cross the BBB (in meningitis); Imipenem metabolized into a nephrotoxic metabolite in the PCT, so combined with cilastatin, to avoid such toxicity and renal problems.
• Spectrum: very wide, active against Gram-positive, Gram-negative, aerobes, and anaerobes.
• Indications: serious hospital-acquired (nosocomial) infections.
• Adverse effects: Allergy, Gastrointestinal (GI) disturbances, seizures.

Monobactams

• Member: Aztreonam.
• Source: Synthetic.
• Chemistry: Beta-lactam antibiotic.
• Pharmacokinetics: Given IM or IV, and excreted in the urine.
• Action: Bactericidal, inhibiting cell wall synthesis (PBP3).
• Spectrum: Narrow, active on Gram-negative bacteria (including Pseudomonas), inactive against Gram-positive and anaerobes.
• Indications: Patients allergic to penicillins.
• Adverse effects: GI disturbances (generally).

Vancomycin

• Source: Natural.
• Pharmacokinetics: Not absorbed orally; IV for systemic infections; weakly crosses the BBB, except in meningitis; largely excreted unchanged in urine; adjust dose in renal impairment.
• Spectrum: Gram-positive bacteria (including MRSA, Clostridium difficile, and Enterococci).
• Indications: Chemoprophylaxis against endocarditis in penicillin-allergic patients; treatment of pseudomembranous colitis, MRSA infections, and UTIs.
• Adverse effects: Ototoxicity, nephrotoxicity, red man syndrome (rapid IV infusion).

Beta-Lactamase Inhibitors

• Some beta-lactam antibiotics are combined with inhibitors to overcome bacterial resistance. Clavulanic acid and Tazobactam are some examples. Such examples include combination with ampicillin, amoxicillin, or piperacillin.