Pharmacology Quiz: Antimicrobials 1-7

Glycopeptides and Lipopeptides

• Vancomycin is often used as a last resort to treat methicillin-resistant Staphylococcus aureus (MRSA) bacteria.
• Bacteria rarely develop resistance to glycopeptides and lipopeptides.
• Glycopeptides and lipopeptides are unstable and mostly administered intravenously (IV), except for Clostridium difficile, which can be treated orally.
• Examples of glycopeptides and lipopeptides include Vancomycin, Teicoplanin, and Daptomycin.
• Mechanism of action: inhibit bacterial cell wall biosynthesis by attaching to the D-ALA-D-ALA terminus of peptidoglycan precursor units, inhibiting transglycosylase and transpeptidase enzymes.
• Resistance occurs through alteration of the D-ALA-D-ALA target, resulting in Vancomycin-resistant enterococci (VRE) and Vancomycin-resistant Staphylococcus aureus (VRSA).
• Adverse effects: ototoxicity, nephrotoxicity, flushing (Redman syndrome), and neutropenia.

Polymixin Antibiotics

• Examples of polymixin antibiotics include Polymixin B and Colistimethate (Polymixin E).
• Mechanism of action: targets bacterial cell wall and outer membrane, binding to the phosphate group of the cytoplasmic membrane and disrupting its integrity.
• Not absorbed from the GI tract, used for gut sterilization and topical treatment of ear, eye, or skin infections.
• Clinical use: effective against Gram-negative bacilli, especially Pseudomonas aeruginosa.
• Adverse effects: nephrotoxicity.

Fosfomycin

• Mechanism of action: inhibits peptidoglycan synthesis by inactivating the enzyme MurA.
• Clinical use: effective against UTI and bladder infections caused by Escherichia coli, Enterococcus faecalis, and Proteus mirabilis.
• No known adverse effects.

Sulfonamides

• Purpose: stops folic acid synthesis, which is required for bacterial DNA and RNA synthesis.
• Examples of sulfonamides include Sulfanilamide, Sulfamethoxazole, Sulfasalazine, Sulfadiazine, and Sulfadoxine (used as an anti-malarial).
• Mechanism of action: competitively inhibit dihydropteroate synthetase (DHPS), stopping folic acid synthesis.
• Adverse effects: hepatitis, hypersensitivity reactions, bone marrow depression, acute renal failure, and cyanosis.

Folic Acid Antagonists

• Purpose: stops folic acid synthesis, which is required for bacterial DNA and RNA synthesis.
• Examples of folic acid antagonists include Trimethoprim and Pyrimethamine.
• Mechanism of action: inhibit bacterial dihydrofolate reductase (DHFR), stopping folic acid synthesis.
• When combined with sulfonamides, they potentiate the action of decreasing bacterial DNA/RNA synthesis.
• Adverse effects: folate deficiency, megaloblastic anemia.

β-Lactam Antibiotics

• Purpose: target peptidoglycan synthesis.
• Mechanism of action: inhibit enzymes processing the developing peptidoglycan layer, selectively and irreversibly inhibiting penicillin binding proteins (PBPs).
• Examples of β-lactam antibiotics include Penicillins, Cephalosporins, Carbapenems, and Monobactams.
• Resistance: β-lactamases, produced by bacteria, catalyze the hydrolysis of the β-lactam ring, inactivating the antibiotic.

Penicillins

• Prototype penicillins: sensitive to β-lactamase, including Penicillin G (benzylpenicillin) and Penicillin V (Phenoxymethylpenicillin).
• Narrow-spectrum penicillins: resistant to β-lactamase, including Methicillin, Oxacillin, Cloxacillin, and Dicloxacillin.
• Broad-spectrum penicillins: sensitive to β-lactamase, including Ampicillin and Amoxicillin.
• Extended-spectrum penicillins: sensitive to β-lactamase, including Carbenicillin.
• β-lactamase inhibitors: allow penicillins to reach their site of action, including Clavulanic acid and Sulbactam.
• Indications: bacterial meningitis, bone and joint infections, skin/soft tissue infections, pharyngitis, bronchitis, pneumonia, urinary tract infections, and sexually transmitted infections.
• Pharmacokinetics: mostly eliminated via renal tubular secretion.
• Adverse effects: hypersensitivity reactions, anaphylactic shock, proconvulsant effect, and general hypersensitivity.

Cephalosporins

• Mechanism of action: irreversible inhibition of penicillin binding proteins (PBPs).
• Indications: septicemia, pneumonia, meningitis, biliary tract infections, urinary tract infections, and sinusitis.
• Pharmacokinetics: wide distribution within the body, can cross the blood-brain barrier.
• Adverse effects: nephrotoxicity, drug-induced alcohol intolerance, bone marrow suppression, and contraindicated in individuals with penicillin-induced anaphylaxis.

Carbapenems

• Characteristics: very broad spectrum of antimicrobial activity, functional features of best β-lactam antibiotics, and β-lactamase inhibitors.
• Examples: Imipenem, Meropenem, and Ertapenem.
• Pharmacokinetics: Imipenem is inactivated by renal dipeptidases (co-prescribed with cilastatin).
• Adverse effects: neurotoxicity (seizures with Imipenem).

Monobactams

• Characteristics: spectrum of activity is almost exclusively devoted to Gram-negative microorganisms, irreversible inhibitor of PBP3.
• Example: Aztreonam.
• Mechanism of action: irreversible inhibitor of PBP3.
• Pharmacokinetics: none to know.
• Adverse effects: inflammation at infusion site (arthralgia and myalgia).

Macrolides

• Spectrum of activity: similar to penicillins, safe alternatives for penicillin-hypersensitive individuals.
• Examples: Erythromycin, Clarithromycin, Azithromycin, and Telithromycin.
• Mechanism of action: bind to the 23S rRNA molecule of the 50S ribosomal subunit, inhibiting peptidyl transferase.
• Pharmacokinetics: can lead to significant inhibition of CYP450.
• Adverse effects: cholestatic jaundice (if treatment is more than 2 weeks).

Chloramphenicol

• Spectrum of activity: bacteriostatic against Gram-negative and Gram-positive organisms, reserved for serious infections.
• Mechanism of action: binds to the 23S rRNA molecule of the 50S ribosomal subunit, inhibiting peptidyl transferase.
• Adverse effects: severe depression of bone marrow causing pancytopenia, 'Grey baby' syndrome.

Oxazolidinones

• Spectrum of activity: active against a wide variety of Gram-positive bacteria, useful against drug-resistant bacteria.
• Example: Linezolid.
• Mechanism of action: inhibits bacterial protein synthesis via antagonism of the N-formylmethionyl-tRNA binding to the 70S ribosome.
• Pharmacokinetics: none to know.
• Adverse effects: thrombocytopenia, serotonin syndrome, and hyperlactatemia.

Fusidic Acid

• Mechanism of action: inhibits bacterial protein synthesis by interfering with translation.
• Pharmacokinetics: none to know.
• Adverse effects: jaundice.

Streptogramins

• Mechanism of action: inhibits bacterial protein synthesis by binding to the 50S subunit of the bacterial ribosome.
• Pharmacokinetics: none to know.
• Adverse effects: inflammation at infusion site (arthralgia and myalgia).

Clindamycin

• Mechanism of action: inhibits bacterial protein synthesis by binding to the 23S rRNA molecule of the 50S ribosomal subunit, inhibiting peptidyl transferase.
• Pharmacokinetics: none to know.
• Adverse effects: potentially lethal pseudomembranous colitis.

Quinolones

• Spectrum of activity: effective against both Gram-positive and Gram-negative bacteria, most effective against Gram-positive bacteria.
• Examples: Nalidixic acid, Ciprofloxacin, Levofloxacin, Ofloxacin, Norfloxacin, and Moxifloxacin.
• Mechanism of action: inhibits topoisomerase II and topoisomerase IV, preventing negative supercoiling of DNA required for transcription or replication.
• Pharmacokinetics: none to know.
• Adverse effects: none to know.

Tetracyclines

• Spectrum of activity: effective against Gram-positive and Gram-negative bacteria, Mycoplasma, Rickettsia, and Chlamydia, also effective against protozoa.
• Examples: Tetracycline, Oxytetracycline, Demeclocycline, Doxycycline, Minocycline, and Tigecycline.
• Mechanism of action: binds reversibly to the 16S subunit of the 30S rib### Antimycobacterial Agents for Tuberculosis (TB)
• First-line agents for TB:
  • Isoniazid
  • Rifampicin
  • Ethambutol
  • Pyrazinamide
• Second-line agents for TB:
  • Capreomycin
  • Cycloserine
  • Streptomycin
  • Note: These agents are used to treat infections likely to be resistant to first-line agents or when first-line agents are abandoned due to adverse effects.

Isoniazid

• Mechanism of action: Prodrug activated by bacterial enzymes (katG) to inhibit synthesis of mycolic acids, which are important components of the mycobacterium cell wall.
• Adverse effects: Hemolytic anemia

Rifampicin (Rifampin)

• Mechanism of action: Binds to and inhibits DNA-dependent RNA polymerase only in prokaryotic cells, thus preventing translation of mRNA into protein.
• Adverse effects: Acute interstitial nephritis (rare), orange tinge to saliva, tears, and sweat.

Ethambutol

• Mechanism of action: Inhibits arabinosyl transferase to impair mycobacterial cell wall synthesis.
• Adverse effects: Optic neuritis (red-green color blindness), peripheral neuropathy

Pyrazinamide

• Mechanism of action: Analog of nicotinamide, converted to pyrazinoic acid, which inhibits bacterial fatty acid synthesis by inhibiting fatty acid synthase.
• Adverse effects: Gout, hepatic damage

Second-line agents for TB

• Capreomycin:
  • Mechanism of action: Peptide antibiotic that binds to the 70S ribosomal unit and inhibits protein synthesis.
  • Adverse effects: Kidney damage, auditory nerve injury (can lead to deafness and ataxia)
• Cycloserine:
  • Mechanism of action: Competitively inhibits bacterial cell wall synthesis by preventing formation of tripeptide sidechains of N-acetylmuramic acid.
  • Adverse effects: None to know
• Bedaquiline:
  • Mechanism of action: Inhibits ATP synthase in mycobacteria.
  • Note: First-in-class diarylquinoline agent for multi-drug resistant TB.
• Delamanid:
  • Mechanism of action: Cell-wall active nitro-dihydroimidazooxazoles that inhibit the synthesis of mycolic acids.
  • Note: Prodrug activated by mycobacterial nitroreductases.

Leprosy

• Definition: Ancient disease that causes chronic disfiguring illness with long latency.
• Two types: Paucibacillary or Multibacillary.
• Spread: Person-to-person through nasal droplets and secretions.
• Antimycobacterial agents for leprosy:
  • Rifampicin
  • Dapsone
  • Clofazimine

Rifampicin (for leprosy)

• Mechanism of action: Binds to and inhibits DNA-dependent RNA polymerase only in prokaryotic cells.
• Adverse effects: Acute interstitial nephritis (rare), orange tinge to saliva, tears, and sweat.

Dapsone

• Mechanism of action: Chemically related to sulfonamides, likely acts by inhibiting bacterial folate synthesis.
• Adverse effects: Hemolysis of red blood cells, methemoglobinemia, lepra reactions.

Clofazimine

• Mechanism of action: Proposed to act on DNA, maybe anti-inflammatory.
• Adverse effects: Reddish color of the skin, urine.

Antifungals

• Naturally occurring antifungal antibiotics:
  • Polyenes
  • Echinocandins
• Synthetic drugs:
  • Azoles
  • Fluorinated Pyrimidines

Amphotericin

• Mechanism of action: Acts on the fungal cell membrane, creating a transmembrane ion channel, resulting in loss of intracellular K+ and disrupting cellular permeability and transport systems.
• Adverse effects: Hypotension, renal toxicity, hypokalemia, thrombocytopenia.

Nystatin

• Mechanism of action: Similar to Amphotericin.
• Adverse effects: Nausea, vomiting, diarrhea.

Griseofulvin

• Mechanism of action: Binds to fungal microtubules and interferes with mitosis.
• Adverse effects: Photosensitivity.

Echinocandins

• Mechanism of action: Inhibit 1,3-β-glucan synthase to impair 1,3-β-glucan production, necessary for structural integrity of the fungal cell wall.
• Examples: Caspofungin, anidulafungin, micafungin.
• Adverse effects: Hepatotoxicity (Micafungin).

Azoles

• Mechanism of action: Inhibit the fungal cytochrome P450 3A enzyme, preventing ergosterol formation from lanosterol, and impairing replication.
• Examples: Ketoconazole, Fluconazole, Itraconazole, Miconazole.
• Adverse effects: Stevens-Johnson syndrome (fluconazole and itraconazole), gynecomastia (ketoconazole).

Flucytosine

• Mechanism of action: Converted to 5-fluorouracil (only within fungal cells), which inhibits thymidylate synthetase and subsequent DNA synthesis.
• Adverse effects: Neutropenia, alopecia, hepatitis.

Terbinafine

• Mechanism of action: Inhibits squalene epoxidase, required for synthesizing ergosterol from squalene.
• Adverse effects: Arthralgia (joint pain), myalgia (muscle pain), hepatitis.

Naftifine

• Mechanism of action: Inhibits squalene epoxidase, required for synthesizing ergosterol from squalene.
• Adverse effects: None to know.

Antihelmintics

• Benzimidazoles:
  • Mebendazole
  • Tiabendazole
  • Albendazole
  • Mechanism of action: Inhibits polymerization of helminth β-tubulin, interfering with microtubule-dependent functions like glucose uptake.
  • Indications: Enterobius vermicularis (pinworm), Trichuris trichiura (whipworm), Ascaris lumbricoides (common roundworm), Ancylostoma duodenale (common hookworm), Necator americanus (American hookworm).
  • Adverse effects: GI disturbances.

Nitazoxanide

• Mechanism of action: Inhibits pyruvate:ferredoxin oxidoreductase (PFOR) enzyme-dependent electron transfer, crucial for parasite anaerobic energy metabolism.
• Indications: Giardiasis, Cryptosporidiosis.
• Adverse effects: Pruritis.

Praziquantel

• Mechanism of action: Binds to protein kinase C-binding sites in schistosome (flukes) voltage-gated calcium channels, inducing Ca2+ influx and leading to parasite paralysis and death.
• Indication: Flukes, Onchocerciasis.
• Adverse effects: Dizziness, abdominal distress.

Levamisole

• Mechanism of action: Nicotine-like action stimulates and subsequently blocks neuromuscular junctions, leading to paralyzed worms being expelled in the feces.
• Indication: Infections by the common roundworm (A.lumbricoides).
• Adverse effects: Agranulocytosis, withdrawn from North American markets.

Ivermectin

• Mechanism of action: Semisynthetic agent derived from avermectin, kills worm by opening glutamate-gated chloride channels, increasing Cl- conductance, and binding to GABA receptors or novel allosteric sites on acetylcholine nicotinic receptor.
• Indications: First choice for treating many filarial infections, active against some roundworms (not hookworms).
• Adverse effects: Skin rash/itching, post-treatment encephalopathy.

Proguanil

• Mechanism of action: Acts as a DHFR inhibitor.
• May also have an effect on the initial hepatic stage.

Atovaquone

• Mechanism of action: Acts on the mitochondrial cytochrome bc1 complex, inhibiting the electron transport chain, and decreasing mitochondrial membrane potential.
• Clinical uses: Highly selective for the active asexual blood stage.
• Mechanism of action: Works synergistically with other drugs.

Antibiotics

• Tetracycline and Doxycycline:
  • Mechanism of action: Inhibit protein translation in the parasite plasmid.
  • Clinical uses: Useful in treating malaria, often used for short-term chemoprophylaxis.
  • Adverse effects: None to know.

Quinolines and Related Compounds

• Mechanism of action: Inhibit heme polymerization, generation of free radicals, and blockage of hemoglobin proteolysis.
• Examples: Chloroquine, Quinine, Quinidine.
• Adverse effects: Cinchonism, hypoglycemia, cardiac dysrhythmias, and fibrillation.

Chloroquine

• Mechanism of### Protozoa Infections

• Amoebiasis: caused by Entamoeba organisms, with Entamoeba hystolytica being the main organism of concern.

• Trypanosomiasis: caused by pathogenic flagellate protozoa, including Trypanosoma brucei, which causes African sleeping sickness, and Trypanosoma cruzi, which causes Chagas disease.

• Leishmaniasis: caused by flagellate protozoa spread by the sandfly.

• Trichomoniasis: caused by Trichomonas vaginalis.

• Giardiasis: caused by ingesting food or water contaminated with fecal matter containing cysts from Giardia lamblia.

• Cryptosporidiosis: caused by the coccidian protozoal species Cryptosporidium parvum and Cryptosporidium hominis.

• Toxoplasmosis: caused by Toxoplasma gondii, with the cat being the definitive host.

Protozoa Medications

Metronidazole

• Belongs to the nitroimidazole antibiotics class.
• Clinical uses: trichomoniasis, amoebiasis, and giardiasis.
• Mechanism of action: requires reductive activation of the nitro group to a reactive radical anion by susceptible anaerobic organisms.
• Side effects: rare neurotoxicity (encephalopathy and ataxia).

Iodoquinol

• Description: orally administered to eliminate intestinal E. histolytica, but not effective on tissue trophozoites.
• Mechanism of action: unknown.
• Side effects: optic atrophy, permanent loss of vision.

Paromomycin

• Description: aminoglycoside of the neomycin/kanamycin family.
• Clinical uses: cryptosporidiosis, giardiasis, and trichomoniasis, as well as intestinal colonization with E. histolytica.
• Mechanism of action: binds irreversibly to the 30S ribosomal subunit, inhibiting protein synthesis.
• Side effects: nephrotoxicity and ototoxicity.

Nitazoxanide

• Description: oral antiparasitic and antiviral agent.
• Clinical uses: treatment of giardiasis and cryptosporidiosis.
• Mechanism of action: inhibits pyruvate:ferredoxin oxidoreductase (PFOR) enzyme-dependent electron transfer.

Co-Trimoxazole

• Description: combination therapy of sulfamethoxazole (sulfa antibiotics) and trimethoprim (folic acid antagonist).
• Clinical uses: first-line treatment for toxoplasmosis and Pneumocystis pneumonia.

African Sleeping Sickness

• Caused by two subtypes of Trypanosoma brucei: Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense.
• Transmission: through the bite of infected tsetse flies.
• Symptoms:
  • Skin: bump at the site of the tsetse fly bite.
  • Blood/Lymph Nodes: fevers, chills, headache, muscle/joint pain.
  • Brain/Cerebrospinal Fluid: persistent headaches, worsening drowsiness, loss of concentration, balance issues.

Chagas Disease

• Caused by Trypanosoma cruzi infection.
• Transmission: through the bite of infected kissing bugs or through contaminated food and water.
• Symptoms:
  • 1st stage: swollen red bump at the bite wound or swelling around the eye.
  • 2nd stage: latent period with no symptoms, despite protozoa still present in the body.
  • 3rd stage: affecting the heart and digestive system.

Treatment of Trypanosomiasis and Chagas Disease

Suramin

• Treats early stage of sleeping sickness.
• Mechanism of action: binds to plasma proteins and enters the parasite via endocytosis, inhibiting key enzymes.
• Side effects: renal toxicity and leukopenia.

Pentamidine

• Treats early stage of sleeping sickness.
• Mechanism of action: inhibits DNA and protein synthesis.
• Side effects: hypoglycemia.

Melarsoprol

• Treats late stage of sleeping sickness.
• Mechanism of action: inactivates enzymes by interacting with protein sulfhydryl groups.
• Side effects: encephalopathy and immediate fatality in some cases.

Eflornithine

• Treats late stage of sleeping sickness.
• Mechanism of action: inhibits parasite ornithine decarboxylase (ODC) enzyme.
• No mentioned side effects.

Nifurtimox and Benznidazole

• Treat Chagas disease.
• Mechanism of action: generate nitro free radicals that kill the parasite.