Chapter 12: Drugs, Microbes, Host -- The Elements of Chemotherapy

Terminology of Chemotherapy

  • Chemotherapeutic drug: chemical used in treatment, relief, or prophylaxis of disease.
    • Prophylaxis: a process that prevents infection or disease in a person at risk.
  • Antimicrobial chemotherapy: chemotherapeutic drugs given as means to control infection.
  • Antimicrobic: all antimicrobial drugs, regardless of origin.
    • Antibiotics: substances produced by the natural metabolic processes of some microorganisms that can inhibit or destroy other microorganisms.
    • Synthetic: derived in the laboratory from dyes or other organic compounds, through chemical reactions.
    • Semi-synthetic: antibiotics that have been modified in the laboratory.
  • Spectrum
    • Narrow spectrum: effective against limited array of different microbial types.
    • Broad-spectrum: agents active against a wider range of different microbes.

Interactions Between Drug and Microbe

  • Selectively toxic: should kill or inhibit microbial cells without damaging host tissues.
  • Cell Wall
    • Most bacteria contain a rigid girdle of peptidoglycan.
    • Penicillins and cephalosporins with one or more enzymes required to complete synthesis of peptidoglycan.
    • Antimicrobial drugs targeting cell wall are usually bactericidal and work on young, growing cell since older cells have stop synthesizing peptidoglycan.
    • Cycloserine inhibits formation of peptidoglycan subunits.
    • Vancomycin hinders the elongation of the peptidoglycan.
  • Nucleic Acid Synthesis
    • Drugs interfere by blocking synthesis of nucleotides, inhibiting replication, or stopping transcription.
    • Sulfonamides
      • Synthetic drugs that interfere with an essential metabolic process in bacteria by acting as metabolic analogs.
        • Metabolic analogs: mimic natural substrate of an enzyme and vie for its active site.
      • Sulfa drugs very similar to metabolic compound PABA (para-aminobenzoic acid) used to synthesize coenzyme tetrahydrofolic acid, which participates in synthesis of purines and certain amino acids.
      • Humans not affect by sulfa drugs due to nutritional needs, humans can't synthesize tetrahydrofolic acid which bacteria do.
    • Trimethoprim
      • A metabolic analog drug that blocks synthesis of purine and pyrimidine 
      • Given often simultaneously with sulfonamides for synergistic effect.
    • Chloroquine
      • Antimalarial drug that binds and crosslinks the double-helix .
      • Quinolones, newer broad spectrum drug, inhibit DNA by unwinding enzymes or helicases and stopping DNA transcription.
    • Azidothymidine (AZT) and Acyclovir
      • Drugs that acts as analogs of purine and pyrimidine and insert into viral nucleic acid and block further replication.
  • Translation
    • Inhibitors react with the ribosome-mRNA (target 30S and 50S subunit).
    • Potential to damage mitochondrial ribosomes which are similar to prokaryotic ribosomes.
    • Aminoglycosides (streptomycin, gentamicin)
      • Insert on sites on the 30S subunit and cause misreading of the mRNA.
    • Tetracycline
      • Block attachment of tRNA on the A acceptor site and stop further synthesis.
    • Chloramphenicol
      • Attaches to sites on 50S subunit that prevents the formation of peptide bonds.
    • Erythromycin
      • Inhibits translocation of the subunit during translation.
  • Cell Membrane
    • Polymyxins
      • Interact with membrane phospholipids, distort cell surface, and cause leakage of proteins and nitrogen bases, particularly of gram negative bacteria.

The Acquisition of Drug Resistance

  • Drug resistance: an adaptive response in which an organism begins to tolerate an amount of drug that would normally be inhibitory.
  • Resistance (R) factor: resistance from intermicrobial transfer of plasmids.
    • Transfered through conjugation, transformation, or transduction.
  • Mechanisms of Drug Resistance
    • 1. Synthesis of enzymes that inactivate drug.
      • Beta-lactamases, hydrolyze the beta-lactam ring structure of some penicillins and cephalosporins.
        • Large number of gram negative species have natural occurring beta-lactamase.
      • Penicillinase, some strains of S. aureus, makes penicillin inactive.
        • Some strains of Neisseria gonorrhoeae produce penicillinase (PPNG).
    • 2. Decrease cell permeability and uptake of the drug.
      • Outer membrane of gram negative cell walls is a natural blockade of some penicillin drugs.
      • Multidrug resistant (MDR) pumps: actively transport drugs and other chemicals out of the cell.
        • Pumps are proteins encoded by plasmids of chromosomes.
        • Confer drug resistance on many gram positive (Staphylococcus, Streptococcus) and gram negative (Pseudomonas, E. coli).
        • Pumps can expel broad range of antimicrobial drugs, detergents, and other toxic substance.
    • 3. Change of drug receptor sites.
      • Microbes alter nature of the specific target drugs use.
    • 4. Change in essential metabolic pathway.
      • Alternative pathway can be made or enzyme or shutting down certain metabolic pathways.
    • Others
      • Lapse into dormancy.
      • Convert to a cell-wall-deficient form (L form) that penicillin cannot affect.
  • Natural Selection and Drug Resistance
    • Drugs offer selective pressure on the population allowing the more "fit" microbe to survive.

Antimicrobic Drug Groups

  • Penicillin and Its Relative
    • Penicillin is a group of antibiotics named for the parent compound and the drugs often end in -cillin.
    • Can be used in unmodified form or semi-synthetic derivatives.
    • Penicillium chrysogenum is the major source of the drug.
    • Important for treating sensitive, gram negative cocci (Streptococcus) and gram positive bacteria (meningcocci and the spirochete of syphilis).
    • Component of Penicillin
      • 1. Thiazolidine ring.
      • 2. Beta-lactam ring.
      • 3. Variable side chain that dictates microbicidal activity.
    • Penicillins G and V are most important natural forms.
    • Semi-synthetic form: ampicillin, carbenicillin, and amoxillin are broad spectrum to treat gram negative enteric rods.
    • Penicillinase resistant penicillin: methicillin, nafcillin, and cloxacillin are good for penicillinase producing bacteria.
    • Mezlocillin and azlocillin have an extended spectrum and are good for combo therapy.
  • Cephalosporin
    • Account for majority of all antibiotics administered.
    • Compounds in cepalosporins isolated from the mold Cephalosporium acremonium.
    • Have similar beta-lactam ring structure as penicillin.
    • Generic names of these compounds often have the root cef, ceph, or kef in their names.
    • Sub-Groups and Uses
      • Broad-spectrum, resistant to penicillinase, and causes fewer allergy reactions.
      • Poorly absorbed from the intestine so most often given parenterally, injected into vein or muscle.
      • First Generation
        • Ex: Cephalothin & Cefazolin
        • Effective against Gram-positive cocci and few Gram-negative.
      • Second Generation
        • Ex: Cefaclor & Cefonacid.
        • Effective against Gram-negative bacteria such as Enterobacter, Proteus, Haemophilus.
      • Third Generation
        • Ex: Cephalexin (Keflex) & cefotaxime.
        • Effective broad-spectrum with well-developed activity against enteric bacteria that produce beta-lactamases.
      • Recent
        • Ceftriaxone (rocephin) is a new semi-synthetic broad-spectrum for wide variety of respiratory, skin, urinary, and nervous system infections.
    • Other Beta-Lactam Antibiotics
      • Imipenem is broad-spectrum for aerobic and anaerobic pathogens active in small concentrations and has few side effects.
      • Aztreonam, isolate from Chromobacterium violaceum, is a narrow-spectrum for pneumonia, septicemia, and unary tract infections from Gram-negative aerobic bacilli.
  • Aminoglycoside
    • Drug composed of 2+ amino sugars and an aminocyclitol (6-carbon) ring.
    • Products from species of soil bacteria in genera Steptomyces and Micromonospora.
    • Inhibit protein synthesis.
      • Broad spectrum as a result.
    • Especially effective against aerobic Gram-negative rods and certain gram-positive bacteria.
    • Streptomycin the oldest of the drugs and replaced with less mammalian toxic drugs.
      • Still used for bubonic plague and tularemia and considered a good antituberculosis agent.
    • Gentamicin is less toxic and widely administered for Gram-negative rods (Escherichia, Pseudomonas, Salmonella, and Shigella).
    • Tobramycin and amikacin are used for bacillary infections and have replaced kanamycin.
  • Tetracycline
    • Derived from a product of Steptomyces called aeromycin which was used to synthesize tetramycin and tetracycline. 
    • Bind to ribosomes and and block protein synthesis.
      • Broad-spectrum as a result.
    • Doxycycline and minocycline are given orally for STDs, Rocky Mountain spotted fever, typhus, Mycoplasma pneumonia, cholera, leptospirosis, acne, and even protozoan infections.
    • Lost cost and easy to administer, but its side effects, GI disruption & deposition in hard tissues, limits use.
  • Chloramphenicol
    • Originally isolated from Streptomyces venezulae.
    • Broad-spectrum with unqique nitrobenzene structure.
    • Blocks peptide bond formation and protein synthesis.
    • No longer derived from natural sources but completely synthetic.
    • Toxic to human cells and cause permanent damage with long-term therapy.
      • Some people have irreversible to bone marrow resulting in aplastic anemia.
      • Drug treatment limited to typhoid fever, brain abscesses, rickettsial and chlamydial infections when alternative treatment is unavailable.
    • Should not be given large doses repeatedly over a long period and blood must be monitored.
  • Erythromycin
    • Isolated from Streptomyces.
    • Consists large lactone ring.
    • Broad-spectrum with low toxicity.
    • Blocks protein synthesis by attaching to ribosomes.
    • Administered orally and preferred drug for Mycoplasma pneumonia, legionellosis, Chlamydia infections, pertussis, and diphtheria and prophylactic drug prior to intestinal surgery.
    • Useful substitute for penicillin resistant streptococci and gonococci and for treating syphilis and acne.
    • Newer semi-synthetic: macrolides clarithromycin and azithromycin useful for middle ear, respiratory, and skin infections as well as approved for Mycobacterium infections in AIDs patients.
      • Clarithromycin has additional applications on controlling infections of stomach ulcers.
  • Clindamycin
    • Broad-spectrum releated to lincomycin.
    • Causes adverse reactions in GI tract.
    • Uses with:
      • Serious infection in large intestine and abdomen due to anaerobic bacteria (Bacteroides & Clostridium) that are unresponsive to other antibiotics.
      • Infections with penicillin resistant staphylococci.
      • Acne medications to skin. 
  • Rifamycin
    • Another product of Streptomycin.
    • Altered to make rifampin.
    • Narrow-spectrum due to inability to pass through the cell-envelope of many gram-negative bacilli.
    • Used primarily for gram-positive rods and cocci and some gram-negative bacteria.
      • Mycobacterial infections, TB and leprosy.
      • Prophylaxis in Neisseria meningitidis carriers and contacts.
      • Occasionally used for Legionella, Brucella, and Staphylococcus infections.
  • Bacillus Antibiotics
    • Bacitracin
      • Narrow-spectrum peptide produced by Bacillus subtilis.
      • Major ingrediant in Neosporin for combating superficial skin infections caused by streptococci and staphylococci.
      • It is usually combined with neomycin (an amingoglycoside) and polymyxin.
    • Polymyxin
      • Narrow spectrum derived from Bacillus polymyxa.
      • Fatty acid component contributes to detergent activity.
      • Polymyxins B and E (colistin) are mainly used in routine application due to toxicity to kidney.
        • Either used for Pseudonomas aeruginosa and severe urinary tract infections caused by other gran-negative rods.
  • New Classes of Antibiotics
    • Fosfomycin Trimethamine
      • Phosphoric agent effective as alternate treatment for UTIs caused by enteric bacteria.
    • Synercid 
      • Combined antibiotic from streptogramin group of drugs.
      • Effective against Staphylococcus and Enterococcus species that cause endocarditis and surgical infections and resistant strains of Streptococcus.
      • Used when all other options are unavailable.

Synthetic Antibacterial Drugs

  • Sulfonamides (sulfa drugs)
    • First modern antimicrobic drugs.
    • Sulfisoxazole best for Shigellosis, acute UTIs, and certain protozoan infections.
      • Effective due to soluability.
    • Silver Sulfadiazine Ointment & Solution
      • Treatment of burns and eye infections.
    • Sulfamethoxazole is given in combination with trimethoprim (Septra, Bactrim) to take advantage of synergistic effect.
      • This combo drug treatment useful for Pneumocystis carinii pneumonia (PCP) in AIDS patients.
    • Sulfones are compounds related to sulfonamides.
      • Most effective form is dapsone, usually given in combination with rifamin and clofazamine over long periods.
  • Isoniazid (INH)
    • Bactericidal to growing cells of Mycobacterium terbuclosis.
    • Ethambutol, a closely related compound, effective in treating the early stages of tuberculosis.
  • Fluoroquinolones
    • Chemically related to quinine.
    • Ideal potency and broad spectrum.
    • Readily absorbed in intestines.
    • Work in minimal concentrations against variety of Gram-positive and Gram-negative bacteria species.
    • Principle quinolones: norfloxacin and ciprofloxacin.
      • Administered for UTIs, STDs, gastrointestinal infections, osteomyelitis, repiratory infections, and soft tissue infections.
    • Newer drugs: sparfloxacin and levofloxacin.
      • Recommended for pneumonia, bronchitis, and sinusitis.
    • Side effects of quinolones include seizures and other brain disturbances.

Agents to Treat Fungal Infections

  • Close similarities with fungal cells and human cells.
  • Four Drug Groups
    • Macrolide Polyene Antibiotics
      • Contain structures that mimic the lipids in some cell membranes.
      • Amphotericin B
        • Amphoteric properties (acidic and basic)
        • Most versatile and effective of all antifungals.
        • Works on most fungal infections including skin and mucous membrane lesions caused by Candida albicans.
        • One of the few drugs that can be used to treat systemic fungal infections such as histoplasmosis and cryptococcus meningitis.
      • Nystatin
        • Used topically or orally to treat candiassis of the skin and mucous membranes.
        • Not useful for subcutaneous or systematic fungal infections or ringworm.
    • Griseofulvin
      • Antifungal product especially active in certain dermatophyte infections such as athlete's foot.
      • Drug is deposited in epidermis, nails, and hair, where it inhibits fungal growth.
      • Relatively nephrotoxic.
    • Synthetic Azoles
      • Broad-spectrum antifungal agent.
      • Ketoconazole
        • Used orally and topically for cutaneous mycoses, vaginal and oral candidiasis, and some systemic mycosis.
      • Fluconazole
        • Used in selected patients for AIDS-related mycoses such as aspergillosis and cryptooccus meningitis.
        • Clotrimazole and miconazole used for topical ointment for infections around mouth, vagina, and skin.
    • Flucytosine
      • Analog of cytosine.
      • Readily dissolved in blood and cerebral fluid.
      • Alone, it can be used to treat cutaneous mycoses.
      • Many fungal infections are resistant and must be combined with amphotericin B to treat systemic mycosis.

Antiparasitic Chemotherapy

  • Antimalarial Drugs: Quinine and Its Relatives
    • Quinine
      • Extracted from bark of cinchona tree.
      • Used for hundreds of years for malaria.
      • Replaced by synthesized quinolines, mainly chloroquine and primaquine due to less toxicity.
        • Primaquine eliminates liver stage.
          • Also given to patients relapsing with malaria.
        • Chloroquine suppresses acute attacks associated with infected RBCs.
  • Other Protozoan Infections
    • Metronidazole (Flagle) effective in treating mild and severe intestinal infections and hepatic diseases caused by Entamoeba histolytica. 
      • Also has applications for Giardia lamblia, and Trichomonas vaginalis.
    • Other Antiprotozoa Drugs
      • Quinicrine, sulfonamides, and tetracyclines.
  • Antihelminthic Drug Therapy
    • Mebendazole and thiabendazole are broad-spectrum antiparasitic drugs used for several roundworms and tapeworms.
      • Inhibit function of microtubes and disrupts glucose utilization.
    • Pyrantel and peperazine paralyze muscles of intestinal roundworms.
    • Newer: praziquantel, a drug to treat various tapeworms and fluke infections.
  • Antiviral Chemotherapeutic Agents
    • Acyclovir (Zovirax) and its relatives are synthetic purine compounds that block DNA synthesis in a small group of viruses (specifically herpesviruses).
    • Acyclovir therapy reduces severity of primary and recurrent genital herpes.
      • Relatives: valacyclovir are more effective.
    • Famciclovir: used to treat shingles and chickenpox.
    • Ribaviran: guanine analog used in aerosol form to treat life-threatening infections by Respiratory Syncytial Virus (RSV) in infants and some viral hemorrhagic fever.
    • Azidothymidine (AZT or Zidovudine) is a thymine analog for AIDS patients.
      • HIV specific by preventing viral reverse transcriptase & blocking further DNA synthesis and viral reproduction.
      • Other drugs: didanosine (ddI), Zalcitabine (ddC), and stavudine (d4T).
    • Relenza & tamiflu effective for influenza B & useful prophylactic.
      • Inhibit the uncoating of the viral RNA.
    • Interferon (IFN)
      • Carbohydrate-containing protein produced principally by fibroblasts & leukocytes in response to various immune stimuli.
      • Antivrial and anticancer properties.

Characteristics of Host-Drug Reactions

  • Toxicity to Organs
    • Terms of Types of Toxicity
      • Hepatoxic (liver)
      • Nephrotoxic (kidneys)
      • Hemotoxic (blood-forming tissue)
      • Neurotoxic (nervous system)
    • Liver responsible for metabolizing and detoxifying foreign chemicals and the liver can be damaged by the drug or its metabolism products.
    • Sulfonamides crystallize in kidney pelvis and form stones that can obstruct the flow of urine.
    • Tetracyclines are contraindicated for children up to 8 years old due to its binding to teeth.
      • Can also pass the placenta for pregnant women.
  • Allergic Response to Drugs
    • Drug can be seen as an antigen to the body and stimulate an allergic response from antibodies.
  • Consideration of Selecting an Antimicrobic Drug
    • Group A streptococci and all anaerobes are known to be uniformly susceptible to penicillin G.
    • Kirby-Bauer technique: method of determining antimicrobic susceptibility by using zone of inhibition as a measurement.
      • E-test: alternative test that uses concentration strips.
    • MIC (Minimum Inhibitory Concentration)
      • Smallest concentration (highest dilution) of drug that visually inhibit growth.
        • Gives smallest effective dose.
    • Narrow-spectrum is best to reduce the potential for a super infection.
    • Therapeutic Index (TI): ratio of dose of the drug that is toxic to humans compared to the minimum effective (therapeutic) dose.
      • (human toxicity dose)/(MIC) = TI
      • Smaller index has greater potential for a toxic reaction.
      • Drugs with higher TI usually is the safest.
    • Combination of aminoglycosides & cephlosporins increase nephrotoxic effects.
Comments