Antimicrobial Drugs Review

First Discoveries

  • WWI Discoveries:
  • Alexander Fleming studied S. aureus, a pathogen that killed many soldiers.
    • Discovered penicillin, a compound produced by a mold contaminating his culture plate, which inhibited the bacteria.
  • 1930s:
  • Prontosil: The first sulfa drug; effective against streptococcal bacteria.
  • Streptomycin: Isolated from Streptomyces griseus; effective against tuberculosis.

Antimicrobial Spectrum

  • Broad-spectrum drugs:
  • Effective against both Gram-positive and Gram-negative bacteria.
    • Examples: Quinolones (Ciprofloxacin, Levofloxacin).
  • Narrow-spectrum drugs:
  • Target a limited range of bacteria.
    • Examples: Bacitracin, Vancomycin (mainly effective against Gram-positive).
  • Bacteriostatic:
  • Prevent bacterial growth by targeting protein synthesis and metabolic pathways.
  • Bactericidal:
  • Actively kill bacteria by targeting cell walls, membranes, or nucleic acids.

Sources of Antimicrobials

  • Antibiotics:
  • Naturally occurring antimicrobial compounds.
  • Synthetic antimicrobials:
  • Manufactured by chemical processes (e.g., Prontosil); help combat antibiotic resistance.
  • Semisynthetic antimicrobials:
  • Naturally occurring antibiotics modified to improve stability or pharmacological actions.
    -Challenges: Difficulties in isolating antibiotics from natural sources lead to gene identification and expression systems for mass production.

Drug Safety

  • Selective Toxicity:
  • Inhibits or kills the target microbe without harming the host cells.
  • Therapeutic Index:
  • Ratio of maximum safe dose to minimum effective dose; a high therapeutic index indicates a safer drug.
  • Toxicity Considerations:
  • Nephrotoxic: Kidney toxicity (e.g., Aminoglycosides).
  • Hepatotoxic: Liver toxicity (e.g., Amoxicillin-clavulanate), causing drug-induced liver injury.

Beta-Lactams

  • Classification:
  • Superfamily of antibacterial drugs that block cell wall construction.
  • Mechanism:
  • Block transpeptidase enzymes, disrupting peptidoglycan cross-linking.
  • Challenges:
  • Beta-lactamases produced by bacteria can inactivate these drugs.
  • Beta-lactamase inhibitors are used alongside beta-lactam drugs to combat this resistance.

Cephalosporins

  • Characteristics:
  • Broad-spectrum and bactericidal, with a large collection of beta-lactam drugs.
  • Allergy considerations:
  • Patients allergic to penicillin may react to first-generation cephalosporins.
  • Generational progress:
  • 5 generations, with increasing activity against Gram-negative and decreasing activity against Gram-positive; only fifth-generation combats MRSA/ORSA (Methicillin-resistant Staphylococcus aureus/oxacillin-resistant Staphylococcus aureus).

Carbapenems

  • Characteristics:
  • Broad-spectrum with low incidence of allergy; only available in injectable forms.
  • Effectiveness:
  • Effective against various multidrug-resistant strains, including carbapenem-resistant Enterobacterales and Pseudomonas aeruginosa.

Monobactams

  • Structure:
  • Contain one ring.
  • Available drug:
  • Aztreonam; it is narrow-spectrum and effective against Gram-negative bacteria like Pseudomonas and Klebsiella, but not useful against Gram-positives.
  • Can usually be given to penicillin-allergic patients.

Glycopeptides

  • Mechanism:
  • Target cell wall construction.
  • Examples:
  • Teicoplanin and Vancomycin; effective against Gram-positive organisms and some resistant strains.
  • Resistance Issues:
  • Vancomycin-resistant strains (e.g., MRSA).
  • Side Effects:
  • Red man syndrome characterized by red flush over the skin.

Quinolones

  • Characteristics:
  • Synthetic antimicrobials targeting DNA replication enzymes (DNA gyrase and topoisomerases).
  • Fluoroquinolones:
  • Modern and widely prescribed; include Ciprofloxacin (effective against Mycobacterium and Pseudomonas) and Levofloxacin (used for Mycoplasma pneumoniae).

Rifamycins

  • History and Use:
  • Originally isolated from bacteria but mainly produced synthetically now; Rifampin is a key example.
  • Inhibits transcription by binding RNA polymerase; used in combination therapy for tuberculosis and leprosy.
  • Effects on other medications:
  • Can inhibit the effectiveness of several drugs (e.g., HIV medications, oral contraceptives).

Macrolides

  • Broad spectrum:
  • Effective against Gram-negative cocci and a range of Gram-positive organisms.
  • Mechanism:
  • Target the 50S subunit of prokaryotic ribosomes.
  • Examples:
  • Erythromycin, Azithromycin, and Clarithromycin.
  • Clinical Use:
  • Treatments include streptococcal infections, chlamydia, and Lyme disease.

Lincosamides

  • Mechanism:
  • Bind to the 50S subunit of ribosomes; broad-spectrum activity.
  • Primary Example:
  • Clindamycin; effective against MRSA and macrolide-resistant infections but may cause colitis from C. difficile.

Phenicols

  • Mechanism:
  • Bind to the 50S ribosomal subunit.
  • Primary Example:
  • Chloramphenicol; effective against various cocci and bacilli, but has a narrow therapeutic index, associated with severe bone marrow toxicity (aplastic anemia).

Tetracyclines

  • Description:
  • Broad-spectrum bacteriostatic drugs, including Tetracycline, Demeclocycline, and Doxycycline.
  • Mechanism:
  • Bind to the 30S ribosomal subunit.
  • Associated with risks like C. difficile infections and adverse effects on bones and teeth in young children.

Aminoglycosides

  • Characteristics:
  • Primarily narrow-spectrum drugs with a poor absorption profile and a half-life of 2-3 hours.
  • Mechanism:
  • Bind to the 30S ribosomal subunit, used primarily against Gram-negative aerobic pathogens.
  • Included Drugs:
  • Neomycin, Streptomycin, Gentamicin, Amikacin, and Tobramycin; can cause irreversible hearing loss and nephrotoxicity.

Antihelminthic Drugs

  • Common Examples:
  • Albendazole and Mebendazole; broad-spectrum drugs targeting glucose uptake and microtubules, effectively treating roundworms and tapeworms.
  • Praziquantel:
  • Targets fluke and tapeworm infections by paralyzing parasites to facilitate their expulsion.

Kirby-Bauer Test

  • Method:
  • Bacteria spread on solid agar (Muller Hinton) with filter paper disks infused with antimicrobial agents.
  • Outcome:
  • Zones of inhibition indicate where bacteria are inhibited from growing.

E-test

  • Method:
  • Similar to Kirby-Bauer but uses a gradient strip to determine Minimum Inhibitory Concentration (MIC), the lowest concentration that inhibits bacterial growth.

Broth Dilution Tests

  • Capabilities:
  • Differentiates between bacteriostatic and bactericidal actions.
  • Minimum Bactericidal Concentration (MBC) is the concentration that kills 99.9% of the bacteria.

Antimicrobial Resistance

  • Definition:
  • When microbes are unresponsive to drug therapy meant to inhibit or eliminate them, leading to the concept of a "superbug" that causes superinfections.

Resistance Types

  • Intrinsic Resistance:
  • Natural resistance factors, like lack of cell wall in M. pneumoniae, biofilm formation, and Gram-negative outer membrane barrier.
  • Acquired Resistance:
  • Arises through genetic mutation or horizontal gene transfer, creating resistant strains that survive drug treatments.