These lecture notes will provide an outline of information from the lectures. They are not complete. They should be used to help follow the lecture and as a guideline for information I think is important. You will need to fill in the gaps.


Chapter 23

 These notes were updated February 18, 2001, and are ready for printing by Spring 2001 Med Micro. students.

I.    Penicillin

A.    Antibiotic produced by Penicillum fungus
B.    Basic structure is a beta-lactam nucleus and several attached groups
C.    Results in weakened bacterial cell wall 1.    Blocks the cross-linking of carbohydrates in peptidoglycan layer during bacterial cell wall formation
2.    This leads to vulnerability to osmotic pressures and subsequent swelling and lysis D.    Is most effective during periods of rapidly multiplying bacteria (log phase of growth)
E.    Active against Gram positive bacteria 1.    Staphylococci, Streptococci, Clostridia, Pneumococci F.    Also used again syphilis spirochetes produce penicillinase (beta-lactamase) 1.    Treponema pallidum G.    In higher concentrations, inhibit Gram negative diplococci 1.    N. gonorrhea and N. meningitis H.    Drawbacks are allergic (anaphylactic) reactions and evolution of penicillin-resistant bacteria 1.    These bacteria produce penicillinase (beta-lactamase) II.   Semisynthetic Penicillins A.    Have broader spectrum o f activity 1.    Include Gram negative rods B.    These are resistant to actions of stomach acid 1.    Thus, are absorbed from the intestine after oral consumption C.    Ampicillin and amoxicillin are excreted through the kidneys and, thus, can be used for UTIs
D.    Other examples include carbenicillin, methicillin, nafcillin, piperacillin, oxacillin, ticarcillin 1.    Ticarcillin is often combined with clavulanic acid, which inactivates penicillinase, and used against organisms resistant to other penicillins E.    Cannot be used if allergy to penicillin exists III.   Cephalosporins A.    Antibiotic produced by Cephalosporium fungus
B.    Similar to penicillins in structure, except beta-lactam nucleus has different composition 1.    Also interfere with bacterial cell wall synthesis C.    Used as alternatives to penicillin 1.    Where there is resistance
2.    Where there is allergy D.    Three generations of this antibiotic 1.    First generation cephalosporins a)    Useful agains Gram positive cocci and some Gram negative rods
b)    Include Keflex and Keflin 2.    Second generation cephalosporins a)    Useful against Gram positive cocci and many Gram negative rodes
b)    Include cefaclor, cefoxitin, and cefuroxime 3.    Third generation cephalosporins a)    Used mainly against Gram negative rods (especially Pseudomonas) and for treating diseases of the CNS
b)    Include Claforan, Rocephin and Fortaz 4.    Fourth generation is under development IV.   Amingoglycosides A.    These are antibiotics that have amino groups bonded to carbohydrate molecules (glycosides) bonded to other carbohydrate molecules
B.    Modus operandi is irreversible attachment to bacterial ribosomes 1.    This blocks the reading of the genetic code on mRNA C.    Must be injected (not absorbed well through digestive system)
D.    Second and third generation cephalosporins and quinolone drugs are preferred to these 1.    Some side effects include possible deafness and kidney damage E.    Examples are streptomycin, gentamicin, neomycin, kanamycin, amikacin, tobramycin, and paromomycin V.    Chloramphenicol A.    First broad-spectrum antibiotic to be discovered 1.    Capable of inhibiting a wide variety of Gram positive and Gram negative bacteria and rickettsiae bacteria
2.    Also works against fungi B.    Works by interfering with protein synthesis in microbes
C.    It crosses the blood-brain barrier 1.    Thus, useful in treating meningitis D.    Drug of choice for typhoid fever
E.    Used as tetracycline alternative to treat ricketssial disorders such as typhus and Rocky Mountain spotted fever
F.    Side effects can be serious 1.    Fatal aplastic anemia
2.    Gray syndrome in newborns VI.   Tetracyclines A.    Broad-spectrum antibiotics with range of activity similar to chloramphenicols
B.    Have four benzene rings in their chemical structure and interfere with protein synthesis by binding to the ribosomes in microbes
C.    Include both natural and semisynthetics
D.    Drug of choice for most rickettsial and chlamydial diseases
E.    Also used against Gram negative bacteria and to treat primary atypical pneumonia, syphilis, gonorrhea, pneumococcal pneumonia, and some protozoal diseases
F.    Side effects include teeth discoloration, stunted bone growth in children, and loss of normal intestinal flora (leading to intestinal Candidiasis) 1.    Not used in pregnant women and children through the teen years VII.   Miscellaneous Antibiotics A.    Macrolides 1.    This group consists of large carbon rings attached to carbohydrate molecules
2.    Work by inhibiting protein synthesis in microbes
3.    Erythromycin is most famous a)    Effective against primary atypical pneumonia and Legionnaires' disease
b)    Used against Gram positive bacteria in patients with penicillin allergy and against Neisseria and Chlamydia
c)    Side effects include GI interference 4.    Clarithromycin is another example a)    Semisynthetic
b)    Binds to ribosomes to inhibit protein synthesis
c)    Works against Gram negative bacteria AND same Gram positive bacteria inhibited by erythromycin
d)    Should not be taken by pregnant women because dangerous to fetal tissue 5.    Another example is azithromycin (Zithromax) a)    Similar mode of action and spectrum of activity
b)    Also dangerous to fetal tissue B.    Vancomycin 1.    Bacterial cell wall inhibitor
2.    Drug of last resort that is administered by IV injection
3.    Used against Gram positive bacteria in severe infections where penicillin allergy or bacterial resistance has developed
4.    Also used against Clostridium and against Enterococcus a)    VRE are vancomycin-resistant enterococci
b)    Synercid (two-drug combination of quinupristin and dalfopristin) was approved recently to be used against resistant strains of S. aureus and S. pneumoniae
c)    This drug combination interferes with bacterial reproduction and is enhanced when used in concert 5.    Side effects include hearing and kidney damage C.    Rifampin 1.    Semisynthetic
2.    Interferes with RNA synthesis in bacteria
3.    Used for TB and leprosy patients, in combination with isoniazid and ethambutol
4.    Also used prophylactically to prevent meningitis caused by Neisseria and Haemophilus
5.    Side effects include liver damage and an orange-red color of the urine, feces, tears, and other body secretions D.    Clindamycin and lincomycin 1.    Alternatives to penicillin where penicillin resistance/allergy is encountered
2.    Serious side effects cause elimination of competitive normal intestinal flora a)    This leads to overgrowth of Clostridium difficile
b)    Once C. difficile overgrow, they begin to produce a toxin that causes pseudomembranous colitis E.    Bacitracin and polymyxin B 1.    Antibiotics produced by Bacillus species
2.    Usually restricted to use on skin a)    Cause kidney damage 3.    Often combined with neomycin in Neosporin VIII.    Antifungals A.    Nystatin 1.    This is an antibiotic produced by Streptomyces B.    Griseofulvin 1.    Used for fungal infections of skin, hair, nails a)    The tinea infections respond to this
b)    Ringworm, athletes foot C.    Amphotericin B 1.    Used for serious systemic fungal infections
2.    Degrades the cell membranes of fungal cells
3.    Drug of last resort, because of serious side effects IX.    Antivirals A.   Amantadine and zanamivir 1.    Prevent the attachment of influenza viruses to the host cell surface B.    Acyclovir, gancyclovir, AZT, and ribavirin 1.    Base analogs a)    Base analogs resemble nitrogenous bases and are erroneously incorporated into viral DNA
b)    The resulting genome cannot replicate itself 2.    AZT and ribavirin are used to treat HIV infections
3.    Acyclovir and gancyclovir are used for herpes infections C.    Other HIV drugs include nevirapine and delavirdine 1.    These bind to and inhibit reverse transcriptase when HIV is replicating D.    Another group of HIVdrugs includes squinavir and ritonavir 1.    These bind to protease, which is needed to form the viral capsid
2.    Called protease inhibitors E.    Interferons are naturally produced by host body cells AFTER infection by the virus 1.    Genetic engineering methods can synthesize artifical interferons a)    Used to treat hepatitis B, genital warts, and one type of leukemia The notes BELOW are taken from the class powerpoint presentation and do not necessarily reflect the text book's presentation of the material.

Antibiotic Use Leads to Antibiotic Resistance

  1. Indiscriminate use of antibiotics
  2. Patients who do not complete their entire regimen of prescribed antibiotics
  3. Widespread use of antibiotics in animal feed
  4. Transfer of plasmid-borne antibiotic resistant genes among bacteria
Some basic vocabulary
  1. Antimicrobial agent
    • Any chemical used to treat a disease caused by a microbe
  2. Antibiotic
    • Any antimicrobial chemical substance produced naturally by microorganisms (such as bacteria/fungi)
  3. Synthetic drugs
    • Chemical drugs made in the laboratory
  4. Semi-synthetic drugs
    • Chemical drugs that are partly made by microorganisms and partly synthetic
The Perfect Antimicrobial
  1. Soluble in body fluids
  2. Selective toxicity that is not easily altered
    • Selective: Kills the pathogen, not the host
    • Not easily altered: Not made more/less toxic by interactions with food, other drugs, or abnormal host conditions (e.g., diabetes, kidney disease, etc.)
  3. Nonallergenic
  4. Stable
    • Maintenance of a constant, therapeutic concentration in blood/tissue fluids
  5. Resistance by microorganisms not easily acquired
  6. Long shelf life
  7. Reasonable cost
Antibacterial agents
  1. Most antimicrobials are antibacterial
    • Keep in mind that some may be simultaneously effective against other types of microbes
  2. Bacteriostatic v.s. bactericidal
The Magic Bullet
  1. To the bacterial cell wall
  2. To the bacterial cell membrane
  3. Against bacterial protein synthesis
  4. Against bacterial nucleic acid synthesis
  5. Against bacterial synthesis of folic acid
Cell Wall
  1. Bacteria are unique in that only they have peptidoglycan cell walls
  2. Antimicrobials directed against peptidoglycan have selective toxicity
    • They either destroy it or block its synthesis
    • This causes lysis of the bacterial cell, which is incompatible with life
    • Eukaryotic cells are UNAFFECTED
    • But...so are wall-less bacteria
    • These are especially effective against Gram positive bacteria
  3. Examples are penicillins, cephalosporins, vancomycin, and bacitracin
Cell membrane
  1. Cell membranes are not unique to bacteria
    • Eukaryotic cells also have a phospholipid bilayer with protein molecules that move freely within it ("fluid mosaic model")
  2. In bacteria, the cell membrane serves as a selectively permeable barrier and as the site of cellular respiration
    • Damage here allows cell leakage to occur and interferes with basic metabolic activities
    • These are especially effective against Gram negative bacteria
  3. Examples are the polymyxins
Ribosomes
  1. These types of antimicrobials work by acting on the bacterial ribosome
    • The prokaryotic ribosome is 70S (30S and 50 S subunit) and the eukaryotic ribosome is 80S
    • HOWEVER, mitochondrial ribosomes in eukaryotic cells have 70S ribosomes, so these are somewhat toxic to eukaryotic cells
  2. Examples are aminoglycosides (such as streptomycin), tetracycline, chloramphenicol, and erythromycin
    • Of these, only the aminoglycosides are bactericidal
Nucleic acid synthesis
  1. Both prokaryotic and eukaryotic cells make nucleic acids
    • BUT some of the essential enzymes necessary to unwinding existing DNA chains ("topoisomerases") and necessary to extending new chains of DNA ("polymerases") are significantly different
    • Other differences exist in how the nucleotides are made in prokaryotic and eukaryotic cells
  2. Examples are rifampin (selectively toxic to bacterial RNA polymerase), the quinolones (selectively toxic to microbial topoisomerase), and flucytosine (a fungicide that is selectively toxic to fungal nucleotide formation)
Folic acid synthesis
  1. Folic acid is an essential vitamin to bacteria
    • Essential here means essential to life
    • Humans do not synthesize folic acid, although it is also essential for them
    • Thus, these antimicrobials have selective toxicity to bacteria
  2. Antimicrobials in this category resemble metabolites that are intermediate in the pathway that produces folic acid
    • They bind competitively to the site, thus inhibiting the production of the final product, folic acid
    • These antimicrobials are also called "antimetabolites"
    • They are bacteriostatic
  3. Examples include the sulfonamides, isoniazid, and trimethoprim
Antifungal agents
  1. Infections are difficult to treat because of similarities between fungal/human cells
  2. Most commonly used antifungals include:
    • Nystatin: selectively toxic because it interacts with ergosterol, a fungal cell membrane sterol not produced by humans
      • Used for vaginal/skin infections (topical) and GI infections (oral, but does not cross intestinal wall)
    • Amphotericin B: Also disrupts fungal cell membranes
      • Used for systemic infections
      • Not selectively toxic, but more destructive to fungal cell membranes
      • Used to treat life-threatening infections such as cryptococcosis and mucormycosis
      • This is the top of the line antifungal
    • Imidazoles, triazoles, flucytosine, griseofulvin
Antiparasitic agents
  1. These are also difficult to treat
    • Not many antimicrobials that are selectively toxic to protozoa and helminths
  2. Mebendazole: roundworms
  3. Metronidazole: Trichomonas vaginalis, Entamoeba histolytica, Giardia lamblia, and certain bacterial infections
  4. Chloroquine: malaria
Antiviral agents
  1. Amantadine: Influenza A
    • Interferes with viral replication at an early stage, probably by uncoating the virus
    • Not very effective once symptoms appear
  2. Acyclovir: DNA viruses of herpes family
    • Resembles guanine and inhibits synthesis of viral, but not human, DNA
  3. Ribavirin: RSV
    • Resembles guanine and inhibits synthesis of viral RNA
  4. Anti-HIV agents
    • Reverse transcriptase inhibitors: AZT (incorporated into growing strand of viral DNA, thus blocking its further growth)
    • Protease inhibotrs: Indinavir, nelfinavir, ritonavir (inhibit HIV protease activity by binding to enzyme’s active site and, thus, stopping viaral replication)
  5. Interferon: chronic viral hepatitis, genital warts, Kaposi’s sarcoma
Side effects
  1. Some are explainable by the similarities between the drug’s target in microbes and human cells; others are not
  2. Three general categories of side effects:
    • Toxicity
      • The less selectively toxic the antimicrobial is, the greater the likelihood of toxicity to the human cells occurring
    • Allergy
      • A condition in which the body’s immune system responds to a foreign substance by forming antibodies
      • Allergic reactions can be limited to mild skin rashes and itching, or they can be life-threatening (anaphylaxis)
    • Disruption of normal microflora
      • Antimicrobial agents, especially broad-spectrum antibiotics, work on both pathogens and indigenous microflora (inhabiting skin, digestive, respiratory, and urogenital tracts; superinfections can then result)
  3. Some believe the development of microbial resistance can be thought of as a side effect
When Prescribing an Antimicrobial, Consider:
  1. Route of administration
  2. In vivo levels that are attainable
  3. Site of infection
  4. Route of excretion
  5. Side effects
  6. Patient overall status
  7. If organism is susceptible to the drug
Drug resistance
  1. Either natural or acquired
    • Some species of microbes are innately resistant to paarticular drugs
    • Occasionally, certain cells of a drug-sensitive species may undergo a genetic change and become resistant
      • This acquired drug resistance is passed on to cells’ progeny, producing a drug-resistant strain
  2. Natural resistance
    • Some species lack antimicrobial drug target
      • Example: Penicillin interferes with peptidoglycan cell wall synthesis; organisms lacking a peptidoglycan cell wall are naturally resistnat
        • These include fungi, protozoa, and wall-less bacteria
      • Example: Most of the penicillins cannot cross the relatively impermeable outer membrane of Gram negative bacteria
        • Thus, Gram negative bacteria are resistant to most penicillins
        • Ampicillin, a semi-synthetic derivative of penicillin, is a broad spectrum antibiotic that affects both Gram positive and Gram negative bacteria
  3. Acquired resistance
    • Mutations and genetic exchange cause this
    • Although antibiotics don’t cause these genetic changes, they favor the resistant strains once the change is in place
    • Either mutations occur on the microbe’s chromosome or it acquires a resistance-conferring plasmid
    • Mechanisms:
      • Acquiring enzymes that can inactivate or destroy the drug
      • Changing the cellular target upon which the drug acts
      • Excluding the drug from the cell or removing it once it has entered
  4. To avoid drug resistance
    • Limit non-medical uses of antibiotics, including animal feed additives
    • Medical use of antibiotics should be more selective and thoughtful
    • Prescribe a course of antibiotics at a high enough dosage and long enough so infection is eradicated
    • Use combined therapy (administering two different drugs at the same time)






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