Drugs, Microbes, Host -- The Elements of Chemotherapy
Terminology of Chemotherapy
Reference: https://sites.google.com/site/rccmicrobiology/chapter-12-drugs-microbes-host----the-elements-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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
Reference: https://sites.google.com/site/rccmicrobiology/chapter-12-drugs-microbes-host----the-elements-of-chemotherapy