PA Antibiotics 2 CWI and PSI

2025 Antimicrobials Part 2

Cell Wall Inhibitors

Introduction

  • Drugs that interfere with bacterial cell wall synthesis.

  • Most effective on proliferating bacteria.

  • Various mechanisms of action (MOA) can lead to resistance against one group of medications but not others.

Bacterial Cell Wall

  • Comprised of Peptidoglycans (N-acetylglucosamine (NAG) + N-acetylmuramic acid (NAM)).

  • Essential functions include growth, protection, nutrient intake, movement, and maintaining shape.

  • Penicillin-binding protein (PBP) is crucial for cross-linking peptidoglycans (transpeptidation) and catalyzing glycan strand (transglycosylation). (Source: Rang & Dale's Pharmacology)

Types of Cell Wall Inhibitors

  1. Beta-lactam Antibiotics

    • Penicillins

    • Cephalosporins

    • Carbapenems

    • Monobactams

  2. Glycopeptide Antibiotics

    • Vancomycin

    • Teicoplanin

  3. Daptomycin

Beta Lactam Antibiotics

  • Characterized by a beta-lactam ring.

  • These antibiotics bind to enzymes necessary for transpeptidation and cross-linking.

  • Ineffective against bacteria lacking cell walls or not actively multiplying.

  • Poor penetration into the intracellular space of human cells.

  • Bacterial resistance can occur via beta-lactamase excretion (chromosomal or plasmid-origin).

  • Generally bactericidal.

Penicillins (Beta-Lactam Antibiotics)

  • First antibiotic used clinically; interferes with cell wall synthesis, leading to cell death.

  • Subtypes include:

    • Natural (G + V)

    • Semisynthetic (Ampicillin)

    • Anti-staphylococcal (Methicillin)

    • Anti-pseudomonal (Piperacillin)

    • Extended spectrum.

  • Effective against:

    • Clostridium perfringens

    • Treponema pallidum

Spectrum and Resistance

  • Active against:

    • Gram-positive cocci (e.g., Streptococcus pneumoniae, faecalis)

    • Gram-positive bacilli (Bacillus anthracis)

    • Gram-negative cocci (Neisseria spp)

    • Some anaerobes (Clostridium perfringens)

  • Resistance mechanisms include beta-lactamase production.

Overcoming Resistance

  • Use beta-lactamase inhibitors to protect antibiotics from degradation.

  • Examples include:

    • Tazobactam

    • Clavulanic acid

  • Pharmacokinetics (PK):

    • Penicillin V (oral use); Penicillin G (parenteral use); penetrates CSF if meninges are inflamed.

Side Effects of Penicillins

  • Hypersensitivity reactions

  • Gastrointestinal disturbances (diarrhea, pseudomembranous colitis)

  • Renal impairment

  • Neurotoxicity (seizures)

  • Hematotoxicity (reduced coagulation)

Cephalosporins (Beta-Lactam Antibiotics)

  • Characterized by different ring structures, more resistant to beta-lactamases.

  • Classified into 5 generations:

    • Most are poorly absorbed orally and primarily eliminated via the kidneys (Ceftriaxone via bile).

    • Cross-reactivity with penicillin exists (3-5%).

Generational Overview

  • 1st Gen: Cefazolin, Cephalexin (substitute for Penicillin G)

  • 2nd Gen: Cefuroxime (covers more Gram-negative bacteria)

  • 3rd Gen: Ceftriaxone, Cefotaxime (effective against meningitis)

  • 4th Gen: Cefepime (aerobic Gram-negative bacteria)

  • 5th Gen: Ceftaroline (broad-spectrum, effective against MRSA).

Carbapenems

  • Broad-spectrum activity, well-absorbed in tissues, IV administration.

  • Caution advised for patients with penicillin allergies.

  • Specific agents:

    • Imipenem: Effective against various Gram-positive, negative, and anaerobic organisms, potential to provoke seizures.

    • Meropenem: Achieves therapeutic levels in the CSF without inflammation.

Monobactams

  • Aztreonam is resistant to beta-lactamases.

  • Effective primarily against Gram-negative bacteria with low cross-reactivity to penicillin.

  • Adverse effects include phlebitis and liver function abnormalities.

Glycopeptide Antibiotics

Vancomycin

  • Effective against MRSA and other resistant Gram-positive organisms.

  • Mechanism: Binds to peptidoglycan precursors to disrupt cross-linking.

  • Side Effects:

    • Nephrotoxicity

    • Infusion reactions (Red Man syndrome)

    • Ototoxicity

Daptomycin

  • Bactericidal; disrupts the plasma membrane.

  • Effective against MRSA and VRE, used for complicated skin infections.

  • Inactivated by pulmonary surfactants, administered IV.

Protein Synthesis Inhibitors

Overview

  • Defined as translation inhibitors, binding to ribosomal subunits to prevent tRNA binding.

Classes of Protein Synthesis Inhibitors

  1. Tetracyclines (e.g., Doxycycline)

    • Bacteriostatic, bind to 30S subunit.

    • Effective against spirochetes, Rickettsia, Chlamydia, Mycoplasma, and H. pylori.

    • Adverse effects: teeth hypoplasia, hepatotoxicity, and severe sunburn.

  2. Glycylcyclines (e.g., Tigecycline)

    • Broad spectrum, including MRSA and resistant streptococci.

    • Last-resort antibiotic; eliminated through the bile.

  3. Aminoglycosides (e.g., Gentamycin)

    • Can be either bacteriostatic or bactericidal depending on concentration, primarily affect aerobic Gram-negative bacteria.

    • Significant for synergistic effects with other antibiotics.

  4. Macrolides (e.g., Azithromycin, Clarithromycin, Erythromycin)

    • Primarily bacteriostatic, affect the 50S ribosomal subunit; used when patients have penicillin allergy.

    • Risk of QT interval prolongation and GI distress.

  5. Lincosamides (Clindamycin)

    • Bacteriostatic for anaerobes and some Gram-positive bacteria.

    • Major risk of C. difficile infection.

  6. Oxazolidinones (Linezolid)

    • Bacteriostatic; effective against Gram-positive, including resistant strains.

    • Associated with serious side effects like thrombocytopenia and peripheral neuropathy.

  7. Chloramphenicol

    • Bacteriostatic; reserved primarily for serious infections such as meningitis.

    • Potentially lethal side effects such as bone marrow suppression, especially in infants (Grey Baby Syndrome).

Antibiotics to Avoid in Pregnancy

  • Tetracycline: Inhibition of bone growth, discoloration of primary teeth.

  • Aminoglycosides: Ototoxicity; hearing loss.

  • Chloramphenicol: Risk of Grey Baby Syndrome.

True or False Questions**

  1. False: Penicillins are bactericidal, not bacteriostatic.

  2. False: Clavulanic acid is used with beta-lactams, not Vancomycin.

  3. True: Penicillin G is commonly prescribed.

  4. True: Penicillins can treat STDs.

  5. False: Penicillins cannot effectively treat C. difficile infections.

(continued with more questions on classifications, efficacy, and resistance mechanisms of antibiotics).