The Elements of Chemotherapy
I.
II.
III.
History of Antimicrobial Agents
A. Sir Alexander Fleming - penicillin
B. Paul Ehrlich – “magic bullet”
C. Gerhard Domagk – sulfanilamide
Origins of Antimicrobial drugs
A. Antibiotics
1. Bacteria-Streptomyces, Bacillus
2. Molds- Penicillium, Cephalosporium
B. Semisynthetics
C. Synthetics
D. Selectively toxic
E. Mechanisms of antimicrobial acation
1. Most antimicrobials are antibacterial
2. Fewer drugs treat eukaryotic infections
3. Fewest antimicrobials for viruses
Targets of antimicrobial drugs
A. Drugs that affect the bacterial cell wall
1. Most contain peptidoglycan
2. Blocking synthesis of peptidoglycan lyses cell
3. Prevents increase in amount of peptidoglycan in growing cells;
no effect on existing peptidoglycan
4. No effect on plant, animal, or protist cells
5. Penicillins, cephalosporin, vancomycin, cycloserine, bacitracin
6. Isoniazid, ethambutol disrupt formation of mycolic acid in
mycobaterial species
B. Drugs that inhibit nucleic acid synthesis
1. May block synthesis of nucleotides, inhibit replication, or stop
transcription
2. Can interfere with function of nucleic acids (nucleotide analogs)
3. Most often used against viruses; also against rapidly dividing
cancer cells
4. Quinolones, fluoroquinolones act against DNA gyrase; little
effect on eukaryotes or viruses
5. Rifampin binds to and inhibits action of RNA polymerase
C. Inhibition of Metabolic Pathways
1. Heavy metals inactivate enzymes
2. Agents that rid body of parasitic worms by paralysis
3. Competitive inhibition-sulfa drugs, trimethoprim (folic acid
pathway)
4. Drugs block activation of viruses
5. Metabolic antagonists
6. Antiviral agents can target unique aspects of viral metabolism
IV.
a. Amantadine, rimantadine, and weak organic bases
neutralize acidity of phagolysosome and prevent viral
uncoating
D. Drugs that block protein synthesis
1. Ribosomes differ in size between prokaryotes and eukaryotes
(except in mitochondria)
2. Aminoglycosides (streptomycin, gentamicin) insert on sites on
30S subunit and cause misreading of mRNA
3. Tetracyclines block attachment of tRNA on the A acceptor site
and stop further synthesis
E. Drugs that disrupt cell membrane function
1. Cells with damaged membranes die from disruption in
metabolism or lysis
2. Drugs have specificity for a particular microbial group, based on
differences in types of lipids in their cell membranes
3. Polymyxins interact with phospholipids causing leakage (G-)
4. Amphotericin B (polyene) and nystatin form complexes with
sterols on fungal membranes (ergosterol) causing leakage
5. Some drugs become incorporated into cytoplasmic membrane
and damage its integrity
Survey of major antimicrobial drug groups
A. Antibacterial antibiotics
1. Penicillins
a. Large diverse group
b. Could be synthesized in laboratory
c. More economical to obtain natural penicillin and modify
d. Penicillium chrysogenum – major source
e. Three parts – thiazolidine ring, beta-lactam ring, variable
side chain dictates microbial activity
f. Penicillins G and V most important natural forms
g. Drugof choice for G+ (streptococci) and some G(meningococci and syphilis spirochete)
h. Semisynthetic-ampicillin, carbenicillin & amoxicillin have
broader spectra; G- enteric rods
i. Penicillin-resistant—methicillin, nafcillin, cloxacillin
j. Problems- allergies, resistant strains of bacteria
2. Cephalosporins
a. Majority of antibiotics administered
b. From Cephalosporium acremonium mold
c. Beta-lactam ring that can be altered
d. Relatively broad-spectrum, resistant to most penicillinases,
cause fewer allergic reactions
e. Some given orally, many administered parenterally
f. Three generations
1) First generation-cephalothin,cefazolin-most
effective against G+ cocci
3.
4.
5.
6.
7.
2) Second generation-cefaclor, cefonacid-more
effective against G3) Third generation-cephalexin, cefotaxime-broad
spectrum activity against enteric bacteria with batalactamases
4) Ceftriaxone-new semisynthetic broad-spectrum
Other beta-lactam antibiotics
a. Imipenem-broad-spectrum drug for infections with aerobic
and anaerobic pathogens
b. Azeotreonam – isolated from bacteria Chromobacterium
violaceum – newer narrow-spectrum fro infections by Gaerobic bacilli
Aminoglycosides
a. Composed of 2 or more amono sugars and an aminocyclitol
(6C) ring
b. Products of various species of soil actinomycetes in
Streptomyces & Micromonospora
c. Broad-spectrum, inhibit protein synthesis, especially useful
against aerobic G- rods and certain G+
d. Streptomycin-bubonic plague, tularemia, TB
e. Gentamicin- less toxic, used against G- rods
f. Tobramycin, amikacin are newer; against GTetracycline
a. Broad-spectrum, block protein synthesis
b. Doxycycline & minocycline- oral drugs taken for STDs,
Rocky Mt. Spotted fever, Lyme disease, typhus, acne,
protozoa
Chloramphenicol
a. Isolated from Streptomyces venezuelae
b. Potent broad-spectrum with unique nitrobenzene structure
c. Blocks peptide bond formation
d. No longer derived from natural source
e. Very toxic, restricted uses, can cuase irreversible damage to
bone marrow (aplastic anemia)
f. Typhoid fever, brain abscesses, rickettsial and chlamydial
infections
Other Streptomyces antibiotics
a. Erythromycin-macrolide, large lactone ring with sugars
1) Broad-spectrum, fairly low toxicity
2) Attaches to ribosome
3) Taken orally for Mycoplasma pneumonia,
legionellosis, Chlamydia, pertussis, diphtheria
4) For penicillin-resistant—gonococci, syphilis, acne
5) Newer semisynthetic macrolides-clarithomycin,
azithromycin
B.
C.
D.
E.
a. Clinamycin – broad-spectrum, serious abdominal anaerobic
infections
b. Vancomycin- narrow-spectrum, effective against penicillin and
methicillin resistant staphylococcal infections; very toxic, hard
to administer (IV only)
c. Rifampin-limited spectrum, cannot pass through many cell
membranes, used to treat G+, TB, leprosy
8. The Bacillus antibiotics
a. Bacitracin- narrow-spectrum peptide produced by Bacillus
subtilis, major ingredient of Neosporin ointment
b. Polymyxin – narrow-spectrum peptide with fatty acid
component, detergent activity; limited by toxicity to
kidney; drug resistant Pseudomanas aeruginosa & UTI
9. New classes of antibiotics
a. Fosfomycin trimethamine- a phosphoric acid effective as
alternate treatment for UTIs, inhibits cell wall synthesis
b. Synercid – effective against Staphylococcus &
Enterococcus that cause endocarditis & surgical infections;
inhibits protein synthesis
Synthetic antibacterial drugs
1. Sulfonamides, sulfa drugs- first antimicrobic drugs
2. Sulfisoxazole-shigellosis, UTI, protozoan infections
3. Silver sulfadiazine- burns, eye infections
4. Trimethoprim – given in combination with sufamethoxazole
Miscellaneous antibacterial drugs
1. Isoniazid-with rifampicin to treat TB
2. Oxazolidinones – new class; inhibits initiation of protein
synthesis; Linezolid-MRSA, VRE
3. Fluoroquinolones- broad-spectrum, potent
a. Norfloxacin, ciprofloxacin-UTI, STD, GI, osteomyletitis
b. Sparofloxacin, levofloxacin-pneumonia, bronchitis
Antifungal drugs
1. Macrolide polyene
a. Amphotericin B – mimic lipids, most versatile & effective,
topical & systemic treatments
b. Nystatin – topical treatment
2. Griseofulvin- stubborn cases of dermatophyte infections,
nephrotoxic
3. Synthetic azoles – broad-spectrum; ketoconazole, clotrimazole,
miconazole
4. Flucytosine – analog of cytosine; cutaneous mycoses or in
combination with amphotericin B for systemic mycoses
Antiparasitic drugs
1. Antimalarial drugs – quinine, chloroquine, primaquine,
mefloquine
V.
VI.
2. Antiprotozoan drugs – Metronidazole (Flagyl), quinicrine,
sulfonamides, tetracyclines
3. Antihelminthic drugs – immobilize, disintegrate, or inhibit
metabolism
a. Mebendazole, thisbendazole – broad-spectrum-inhibit
function of microtubules, interferes with glucose utilization
& disables them
b. Pyrantel, piperazine- paralyze muscles
c. Niclosamide-destroys scolex
F. Antiviral drugs
1. Block penetration into host cell
2. Block transcriptin or translation—nucleoside analogs Acyclovir
(herpesviruses), Ribavirin-guanine analog-(RSV, hemorrhagic
fevers), AZT –thymine analog- (HIV)
3. Prevent maturation of viral particles—protease inhibitors (HIV)
4. Interferon- HCV
Development of Resistant Organisms in Populations
A. Some are naturally partially or completely resistant
B. Resistance by bacteria acquires in 2 ways
1. New mutations of chromosomal genes
2. R-plasmids
C. Resistance to more than one drug at a time
D. Develop in hospitals and nursing homes; constant use of drugs
E. Mechanisms drug resistance
1. Drug inactivation
2. Decreased permeability to drug or increased elimination of drug
3. Change in metabolic patterns
4. Change in drug receptors
F. Retarding resistance
1. High concentrations in patient long enough to kill all sensitive
cells and inhibit others for immune system
2. Use antimicrobial agents in combination
3. Limit use
4. Development of new variations of existing drugs
G. Side effects of drugs
1. Toxicity to organs; kidneys, liver, or nerves
2. Allergic responses; anaphylactic shock
3. Suppression and alteration of microflora
4. Consider when prescribing to pregnant women
H. Disruption of Normal Microbiota
1. Secondary infections
2. Overgrowth of normal flora-superinfections
3. Greatest concern in hospitals
Sensitivity testing
A. Kirby-Bauer---disk diffusion
B. E strip test
VII.
VIII.
C. MIC and MBC
D. Therapeutic index
Considerations in selecting an antimicrobial drug
A. Nature of microbe causing infection
B. Degree of microbe’s sensitivity to various drugs
C. Overall medical condition of patient
Routes of Administering Drugs
A. Topical
B. Oral
C. Intramuscular
D. Intravenous
E. Must know how drug will be distributed to infected tissues