Antimicrobial Chemotherapy

1. Disinfectant, sanitizer, antiseptic, chemotherapeutic agents
   1. Antibiotics: Penicillin, Erythromycin
   2. Semisynthetic drugs: rifampin, chloroquine
   3. Synthetic drugs: Ciprofloxacin, isoniazid
2. Antibacterial effect
   • cidal : Ampicillin, ciprofloxacin
     • some drugs are cidal only vs. growing cells: 
   • static: Streptomycin, tetracycline
   • side effects
3. Specificity:
   1. antifungal: Nystatin, amphothericin B, griseofulvin
   2. antibacterial: Penicillin, streptomycin
   3. antiviral: Amantadine, acyclovir, AZT, nevirapine
   4. antiprotozoan: Chloropquine, metronidazole
4. Spectrum of activity:
   1. Broad-spectrum 
   2. Narrow-spectrum

II. Effectiveness of antimicrobial drugs

1. Selective toxicity

1. Therapeutic dose (ED50)
2. Toxic dose (à side effects): LD50
3. Therapeutic index = LD50/ED50

2.    Measuring tools

1. Disk diffusion (Kirby Bauer) 
2. Broth Dilution susceptibility test
   • MIC
   • MLC
3. Serum killing power

3.    Factors that influence effectiveness

1. Administration route
   • Topical: neomycin, bacitracin
   • Oral: Penicillin V, tetracycline
   • Intramuscular: gentamycin
   • Intravenous: Penicillin G, Vancomycin
2. Drug concentration
   • Bloodstream (free/bound)
   • CNS: difficult to reach
   • Tissues/cells: some drugs must be able to enter cells
   • Drug removal: inactivation, excretion
3. Pathogen susceptibility
4. Pathogen resistance

1.     Penicillins

    

1. Penicillin G
   • b -lactam antibiotic - used vs. systemic infections
   • Few side effects except allergic reactions
   • Staphylococcus, Bacillus anthracis
2. Ampicillin, Amoxicillin, Ticarcillin³, Piperacillin⁴
   • Broad-spectrum semi-synthetic drugs
   • Haemophilus, Pseudomonas
3. Methicillin, Nafcillin, Oxacillin
   • b -lactamase resistant semi-synthetic
   • Staphylococcus*
4. Penicillin V
   • acid resistant - oral administration
   • Streptococcus pneumoniae & pyogenes
2. Cephalosporins
   • Cephalothin, Cefazolin¹, Cefuroxime², Cefotaxime³, Cefepime⁴
   • Broad-spectrum, more effective vs. G+
   • Further activity vs. ¹E. coli, ¹Klebsiella, ²Enterobacter, ²Citrobacter, ^3,4Pseudomonas
   • Staphylococcus*
3. Cephamycins
   • Similar in structure to cephalosporins
   • More b -lactamase resistant
4. Carbapenems (imipenem, meropenem)
   • Broad spectrum b -lactam antibiotic
   • Resistance in oxacillin-resistant bacteria & Pseudomonas
5. Monobactams (aztreonam)
   • Narrow-spectrum b -lactam antibiotic
   • effective vs aerobic Gram-negative bacteria
6. Glycopeptides
   1. Vancomycin
      • Narrow-spectrum: most G+
      • Blocks transpeptidation step at D-ala - D-ala
      • Plasmid-mediated resistance: VanA, VanB (VRE)
      • Staphylococcus*
   2. Teicoplanin
      • Similar to vancomycin in activity
      • Used in Europe
      • More info
7. Polypeptides: Bacitracin
   • Topical use only - extremely toxic if taken systemically
   • Interferes with peptidoglycan transporter in bacterial membranes
8. Anti-mycobacterials
   1. Ethambutol
      • Inhibits mycolic acid incorporation
      • Narrow spectrum antimycobacterial
   2. Isoniazid
      • Inhibits mycolic acid synthesis
      • Narrow-spectrum antimycobacterial

B. Protein synthesis inhibitors

1. Aminoglycosides
   • Streptomycin, gentamycin, kanamycin, neomycin, tobramycin, amikacin
   • High toxicity: damage inner ear, kidneys
   • Do not reach CNS
   • Broad spectrum, bacteriocidal, best vs. G-neg
   • Uptake is aerobic process: not vs anaerobes, abscesses
   • High level of resistance to Streptomycin
   • Streptomycin vs. Yersinia, TB, tularemia
   • Gentamycin vs. Pseudomonas, Klebsiella, E. coli (systemic/kidney infections)
2. Tetracyclines
   • Tetracycline, doxycycline, minocycline
   • Block tRNA binding to 30S
   • Natural/semi-synthetic, broad spectrum, bacteriostatic
   • Side effects include GI pain, diarrhea, stained teeth
   • Rickettsia & Chlamydia & Mycoplasma
3. Glycylcyclines
   • Tigecycline (new)
   • Broad spectrum (except some G-)
4. Macrolides
   • Erythromycin, azithromycin, clarithromycin, telithromycin
   • Relatively narrow spectrum: G+, some G-neg, Chlamydia
   • Bacteriostatic - Block initiation of protein synthesis
   • Mycoplasma, diphtheria, Campylobacter
5. Lincosamides: clindamycin
6. Chloramphenicol
   • Natural and synthetic - Binds  50S subunit
   • Stable, can be taken orally, penetrates well into CNS
   • Some serious side effects: aplastic anemia, death in rare cases
   • Salmonella typhi, Bacteroides
7. Oxazolidinones: Linezolid
   • Novel synthetic drug
   • Inhibits protein synthesis initiation
   • Broad spectrum
   • For use vs. drug-resistant bacteria s.a. VRE, MRSA
8. Ketolides:
   • Telithromycin (new)
   • vs. Staphylococcus, respiratory pathogens, intracellular pathogens
9. Streptogramins
   • Quinupristin-Dalfopristin (new)
   • vs. VR E. faecium

C. Nucleic acid synthesis inhibitors / disruptors

1. Rifampin, rifabutin
   • RNA polymerase inhibitors
   • Mycobacterium, MRSA
2. Quinolones: Ciprofloxacin, nalidixic acid, levofloxacin, moxifloxacin
   • DNA gyrase/topoisomerase inhibitors
   • Broad-spectrum
   • UTIs, Neisseria, Chlamydia, Pseudomonas, anthrax
3. Metronidazole
   • Broad-spectrum vs. anaerobic bacteria, protozoa
   • Disrupt DNA structure; Inhibits DNA repair mechanism?
4. Nitrofurantoin
   • Inhibits mRNA synthesis
   • Used only vs. urinary tract infections (E. coli, Proteus, Klebsiella)
5. Clofazimine
   • Disrupts mycobacterial DNA

D. Cell membrane disruptors

1. Polymyxin B
   • Detergent action
   • Toxic to human cells - limited to topical use
   • Narrow-spectrum vs. Gram-negatives
   • Pseudomonas*
2. Gramicidin
   • Active vs. G+ cells
   • Toxic to human cells
3. Lipopeptides (Daptomycin)
   • Narrow-spectrum vs Gram+
   • Membrane depolarization
   • Active vs. MRSA, VRE
4. Novel class: outer membrane protein inhibitors: Darobactin, Dynobactin

E.  Metabolic inhibitors

1. Sulfonamides: Sulfamethoxasole, sulfisoxasole
   • Folic acid synthesis inhibitor (usually bacteriostatic)
   • Broad spectrum synthetic drug
   • Side effects: mostly allergic reactions
   • Increasing drug resistance make these less useful
   • E. coli (UTIs)
2. Trimethoprim
   • Inhibits folic acid synthesis at different step
   • Often used in combination with sulfamethoxasole
   • Treatment of UTIs (Gram - neg)
3. Dapsone
   • Anti-mycobacterial
4. Pyrazinamide
   • Disrupts membrane transport in Mycobacteria

IV. Antifungal drugs (Table 70-2)

Mode of action

• Interfere with fungal membranes (sterols)
• Interfere with fungal DNA synthesis or cell division

1. Nystatin
   1. Primarily vs. Candida infections
   2. Topical - skin/vaginal
2. Amphothericin B
   1. Very toxic (kidneys), usually administered IV
   2. Used for serious systemic mycoses (Histoplasma, cryptococcus, Blastomyces, Aspergillus)
3. Imidazoles (miconazole, clotrimazole, ketoconazole)
   1. Primarily used as topical agent; available OTC
   2. Vaginal candidiasis, athlete's foot
4. Triazoles (fluconazole, itraconazole, voriconazole, posaconazole)
   1. Inhibit ergosterol synthesis
   2. Less toxic than amphothericin; used systemically
5. Echinocandins (Caspofungin)
   1. inhibit fungal cell wall synthesis
   2. Candida, Aspergillus
6. Flucytosine
   1. cytosine analogue, interferes with fungal DNA synthesis
   2. oral or systemic (with amphothericin) antifungal agent e.g. Candida, Cryptococcus
7. Allylamines (Terbinafine)
   1. Inhibits squalene epoxidase
   2. Dermatomycoses s.a. Sporotrichosis, etc
8. Griseofulvin
   1. Topical antifungal agent; OTC available
   2. Ringworm, athlete's foot
   3. Interferes with fungal cell division

• More information here

V. Antiviral drugs (Table 49-2)

1. Virus integrity
   1. Nonoxynol-9: envelope disruption
   2. Citric acid: disrupts rhinoviruses
2. Uncoating
   1. Amantadine & rimantadine: Influenza A
   2. Pleconaril prevents uncoating of picornaviruses
   3. Enfuvirtide: uncoating of HIV
3. Enzyme inhibitors
   1. Oseltamivir, zanamivir inhibit neuraminidase
   2. Influenza A & B
4. Nucleoside analogues
   1. Acyclovir, famcyclovir, valacyclovir, Ganciclovir
   2. Must first be phosphorylated by a viral enzyme
   3. Effective against replication of dsDNA viruses (Herpes family)
      • Herpes, chicken pox, shingles
      • CMV (Gan, Cid)
   4. Cidofovir, adefovir
      • Need no phosphorylation step - broader spectrum
   5. Remdesivir: COVID-19
5. Block RNA synthesis & replication
   1. Ribavirin: Lassa, RSV
   2. Guanidine: Picornavirus
   3. Interferon
6. Immune system modulators
   1. Interferon (Hepatitis, HPV)
   2. Imiquimod: TLR ligand
   3. IL-1 (e.g. anakinra) and IL-6 (e.g. sarilumab) inhibitors - COVID-19
7. Antiretroviral drugs (HIV)
   1. Zidovudine (AZT), didanosine, zalcitabine, lamivudine, stavudine
      • nucleotide analogues
      • acts as reverse transcriptase inhibitor
   2. Nevirapine, delavirdine, foscarnet
      • reverse transcriptase inhibitors
      • non-nucleoside analogues
   3. indinavir, nelfinavir, ritonavir, saquinavir
      • Protease inhibitors
      • Nirmatrelvir+ritonavir = Paxlovid (COVID-19)
   4. Raltegravir
      • Integrase inhibitor
   5. Enfuvirtide (gp41), Maraviroc (CCR5)
      • Entry/Fusion inhibitor

VI. Antiprotozoan drugs

1. Heavy metals
   1. Arsenic (melarsoprol), Antimony (stibogluconate)
   2. Toxic; parasiticidal
   3. Leishmania, Trypanosoma
2. Metronidazole
   • Effective against Trichomonas, Entamoeba, Giardia, and anaerobic bacteria
3. Quinolines (Chloroquine, quinine, primaquine)
   • Derivative of quinine (naturally occuriing in cinchona bark)
   • Kills Plasmodium inside RBC
4. Folic acid anti-metabolites (trimethoprim, diaminopyrimidine, pyrimethamine, sulfonamide)
   • Toxoplasmosis, Malaria
5. Protein synthesis inhibitors (clindamycin, tetracyclines)
6. Other agents
   • Pentamidine (interferes with DNA?) - Trypanosomes
   • Metronidazole (DNA/RNA synthesis or damage) - Giardia, Trichomonas
   • Artemisinin (damage membrane) - Malaria
   • Malarone (anti-mitochondrial) - Malaria
   • Miltefosine (vs. membrane ether lipids) - Leishmania
   • Nitazoxanide (vs. anaerobic metabolism) - Cryptosporidium, Entamoeba

Reference links for more information

1. http://www.bmb.leeds.ac.uk/mbiology/ug/ugteach/icu8/antibiotics/dna.html
2. http://wordnet.com.au/Products/topics_in_infectious_diseases_Mar01.htm
3. http://www.fungi.com/pdf/pdfs/articles/HerbalGram.pdf
4.