Unit 4
Control of Microbial
Infections
Two ways to control microbial
infections:
1.
attack the
pathogens
chemotherapy
-
other microbes -
2.
shore up host
defenses
immunization
improvements
in sanitation, nutrition, and health
I. Chemotherapy
A. History of Chemotherapy
1854-1915 - Paul Ehrlich -
staining ΰmagic bullet
A chemical with selective
toxicity that would kill the pathogen and not human cells would be an effective
treatment
1904 Ehrlich - a dye called
Trypan Red was active against trypanosomes
1910 Ehrlich - Salvarsan,
an arsenic - against the syphilis spirochete
1935 - discovery that
Prontosil Red a leather dye - was
active against staphylococci and streptococci breaks down in body to a sulfa
drug - synthetic drugs - Gerhard Domagk
1928 - Fleming - discovery
that mold Penicillium would inhibit
growth of staphylococci - first antibiotic **
1940 Florey, Chain, Heatley
- production and purification of penicillin
1944 - streptomycin
discovered by Selman Waksman
1953 - chloramphenicol,
neomycin, tetracycline discovered.
Era of antibiotics begins -
mainstay of txt against infectious disease for about 50 yrs.
B. Concerns for Antimicrobial
Administration, Distribution, and Elimination
1.
Routes of
administration
a. IV - into a vein -
b. IM - into the muscle -
c. oral (
2.
What inhibits
antimicrobial distribution in the body?
a. barriers cell membranes, tight cellular junctions
b. Difficult sites to penetrate
o
CNS
o
eye
o
mammary gland
o
prostate
o
testis
o
intracellular
o
inflammatory
"capsule" (abscess)
3.
How are
antimicrobials eliminated from the body?
a. metabolized into a different compound, usually an
inactive form, in the liver.
b. removed from blood in the kidneys and excreted in the
urine.
c. excreted by liver cells into bile and eliminated in
the feces.
C. How Antimicrobial Agents
Work
Antimicrobials
are classified by two different classification systems used simultaneously:
1. microbicidal or microbistatic - whether they kill or inhibit
the growth -
2. by target site of the drug
Antimicrobial
agents organized by site of action
**5 Sites of Action or
Targets of Antimicrobials
1.
Cell wall
synthesis
2.
Cell membrane
function
3.
Nucleic acid
synthesis or replication
4.
Protein synthesis
5.
Synthesis of
essential metabolites
1. Inhibition of cell wall synthesis
Can inhibit peptidoglycan synthesis in two different
manners:
a. inhibit synthesis of the linear strands Exs.
vancomycin and bacitracin
b. inhibit cross-linking of the strands Ex. Beta-lactams
- penicillins and cephalosporins
2.
Disrupt cell membrane function
a. phospholipids of gram negative bacteria
b. sterols of
eucaryotic fungi - ergosterol
3. Inhibit nucleic acid
synthesis
a.
quinolones inhibit DNA gyrase prevents relaxation of supercoiled DNA during
replication
b.
rifampicin inhibits bacterial RNA polymerase ΰ mRNA synth
4.
Inhibit protein
synthesis - review for yourself the steps in protein synthesis
Targets
of antimicrobial agents that inhibit protein synthesis:
1.
30S subunit
a.
Aminoglycosides
and Streptomycin bind irreversibly to the 30S subunit and prevent formation of
the initiation complex - stop protein synthesis -
b. Tetracyclines also bind to 30S and interfere with attachment
of charged tRNA to the A site of the ribosome - reversible -
2.
50S subunit
a.
Erythromycin and
Chloramphenicol bind reversibly to 50S - inhibit formation of growing
polypeptide chain
5.
Inhibit folic acid synthesis
Two
antimicrobial agents that inhibit folic acid synthesis:
a.
Sulfonamides -
sulfa drugs
b.
Trimethoprim
Inhibit folic acid synthesis in 2 different places.
Trimethoprim inhibits an enzyme - dihydrofolate
reductase
Sulfonamides are competitive inhibitors of folic acid
synthesis
Antimicrobial agents organized by drug
category we will not have a lecture over the following material but you will
need to know it, especially the antibiotics you handle in the lab.
A. Antibacterial Agents fill the blanks for antibacterial in for yourself
as you read the chapter.
1. Beta-lactams antibiotics
containing a beta-lactam ring
a. Penicillins end in illin
b. Cephalosporins begin with ceph or cef
·
Mode of action -
·
Administration
route -
·
Distribution in
the body -
·
Mechanism of
elimination -
·
Special uses -
·
Adverse side
effects -
·
Examples -
penicillin, ampicillin, amoxicillin, methicillin
cephalothin, cephalexin, cefaclor
2. Aminoglycosides end in
mycin or micin
·
Mode of action -
·
Administration -
·
Distribution -
·
Elimination -
·
Uses -
·
Side effects -
·
Examples -
streptomycin, gentamicin, amikacin, neomycin
3. Tetracyclines end in
cline
·
Mode of action -
·
Administration -
·
Uses -
·
Side effects:
GI
children
liver
v Added to animal feed - resulting in widespread
resistance
·
Examples
oxytetracycline, doxycycline
4. Chloramphenicol
·
Mode of action -
·
Administration -
·
Distribution -
·
Elimination -
·
Uses -
·
Side effects -
5. Macrolides, lincosamides -
mycin
·
Mode of action -
·
Administration -
·
Distribution -
·
Elimination -
·
Uses -
·
Examples:
Macrolide - Erythromycin
Lincosamide - Clindamycin
6. Sulfonamides - synthetic
·
Mode of action -
·
Administration -
·
Distribution -
·
Elimination -
·
Uses -
·
Side effects -
·
Example Sulfamethoxazole (GantanoleR)
7. Quinolones /
Fluoroquinolones- synthetic
·
Mode of Action -
·
Administration -
·
Distribution -
·
Elimination -
·
Uses -
·
Side effects
·
Examples - (nalidixic
acid), norfloxacin, ciprofloxacin
B. Anti-Fungals
Fewer
in number
Selective
toxicity more difficult superficial infections respond well to topical
antifungals but systemic fungal infections are challenging to cure.
Examples:
1. Polyenes produced by Streptomyces
· Ex. |
Nystatin |
Amphotericin B |
· Mode of action - |
Both bind to ergosterol in
the fungal membrane ΰ leakage ΰ cell death |
|
·
Administered - |
Topical |
IV |
·
Uses - |
|
Poor penetration into fluids.
Used for serious systemic infections such as cryptococcal meningitis,
histoplasmosis. |
·
Side effects - |
|
Nephrotoxicity ΰ permanent kidney damage in 80% of treated patients. |
2. Azoles lots of them
·
Mode of action inhibit
the synthesis of ergosterol
·
Uses skin and
deep systemic mycoses
·
Exs. miconazole,
ketoconazole, fluconazole
IV PO
3. Griseofulvin from Penicillium
·
Mode of action
impairs mitotic spindle ΰ inhibits fungal cell division
·
Uses dermatophytes
a 1st line txt but being replaced by newer antifungals like the
azoles.
C. Anti Virals Development of antiviral chemotherapy
has lagged behind the others but has been spurred by HIV/AIDS. Since viruses
use host structures and enzymes for replication, inhibiting viral replication
without toxicity to the host is difficult.
Targets for antivirals in
theory, any step from attachment & entry ΰ exit.
1. Inhibit early
viral processes
·
Ex. Amantadine
·
Mode of action
blocks channels in viral envelope ΰ prevents viral uncoating.
·
Administration
·
Uses Protection
from and txt of influenza. Prophylaxis for high risk patients. There is fear
now that Americans will stockpile antivirals against pandemic flu, use them
incorrectly and cause development of antiviral resistance in Influenza virus.
2. Inhibit viral nucleic acid synthesis
·
Ex. Acyclovir (ZoviraxR)
·
Mode of action
interferes with viral polymerase (herpesviruses bring their own
polymerase)
·
Uses herpes,
varicella infections to prevent reactivation & encephalitis can not
resolve latent infections not a cure.
·
Ex. Ribavarin
(VirazoleR)
·
Uses broad
range anti-viral. Used for children w/ severe RSV & adults w/ severe
influenza or measles.
3. Inhibit proteases ΰ formation of defective HIV
·
Ex. saquinavir
(Hoffman LaRoche, FDA approved 95)
·
Never use in
monotherapy due to risk of developing resistance.
4. Inhibit reverse transcriptase - retroviruses
including HIV (RNA ΰ DNA)
·
Ex. AZT =
Azidothymidine (Zidovudine,
RetrovirR)
·
Mode of action
analogue of thymidine, interferes with reverse transcription.
·
Administration
·
Uses slows the
progression of immune failure. Given to pregnant women so they wont pass HIV
to their fetus.
·
Side effects
nausea ΰ bone marrow toxicity
·
Never use in
monotherapy.