CHAPTER 20
ANTIMICROBIAL DRUGS
Chemotherapeutic
drugs (chemotherapy) combat disease in the body, whether it is caused by a
pathogenic microbe or something else (cancer)
An
antimicrobial drug is a chemical that destroys pathogenic microbes with minimal
damage to the tissues of the host—this is selective toxicity.
Antibiotic---this
is specifically a chemical invented by one microbe to work against other
microbes
Synthetic---prepared
in the laboratory, no microbe involved
Semisynthetic-----the
original antibiotic is changed or modified in the lab
1.
Although chemotherapy with natural products such as herbs can be traced back
far in the history of man, Paul Ehrlich is given credit for the birth of modern
chemotherapy. He set out to create a treatment for syphilis that would cure the
disease more reliably and with less harm to the patient than existing
treatments, which involved the use of mercury. His discovery was Salvarsan, a
modified form of arsenic. It was first called Compound 606, because Ehrlich had
tried 605 compounds before it which did not work.
2. In
1928, Alexander Fleming observed that a mold which had appeared as a
contaminant in a Petri dish of bacteria had prevented bacterial growth in the
area surrounding it. The mold was identified as Penicillium notatum. Fleming regarded his discovery as a curiosity
and made little effort to develop it.
3. In
1935, Domagk and Trefoil discovered and developed the antimicrobial properties
of a synthetic red dye called prontosil. Living cells change prontosil into
sulfanilamide, which is antimicrobial. At first, the sulfas were used as a
powder to dust on wounds. Later they were developed into systemic drugs, and derivatives
are widely used today. Since sulfas are synthetic, they are not true
antibiotics.
4. In
1940, Florey and Chain worked with penicillin, the active compound in Fleming’s
discovery, and brought it to clinical trials. At that time, it was extremely
difficult to produce penicillin, but it showed promise. The work was moved to
the
5.
Selman Waksman soon discovered streptomycin, which worked very well against
gram-negative bacteria. At that point, many scientists believed (mistakenly)
that we had won the war against bacteria.
Most
antibiotics come from soil bacteria. A great number of the antibiotics that are
discovered are so toxic that while they kill all known bacteria, they also kill
the patient. Only a small percentage can be developed for use in treating
disease. Some organisms that produce antibiotics are:
1.
Members of the genus Streptomyces (bacteria)--more
than half our antibiotics
2.
Members of the genus Bacillus (bacteria)
3.
Members of the genus Cephalosporium (fungus)
4.
Members of the genus Penicillium (fungus)
TABLE 20.1
P. 582
The goal
that must always be kept in mind is that the antimicrobial must cause more harm
to the pathogen than to the host. This
is called selective toxicity. We have
had our greatest success with antibacterial antibiotics, since there are a
number of things that are different in procaryotic bacterial cells from the
eucaryotic cells of the host. These differences make it relatively easy to
target the pathogen and spare the host. Attacking the eucaryotic cells of
fungi, helminths, and protozoa, and the
host cells that viruses have invaded is more difficult.
Antimicrobials
may work against only certain microbes. They can be:
·
Antibacterial
·
Antifungal
·
Antiviral
·
Antiprotozoal
The
spectrum of activity is the range of different microbes a drug is able to work
against. Narrow-spectrum means that the
drug works best against only a certain group or type; broad-spectrum drugs work
against a wider range of microbes. If the drug works against bacteria, a
broad-spectrum drug would probably do well against both gram-positive and
gram-negative organisms. A narrow-spectrum drug would work only against one or the
other, or possibly an even narrower group.
An ideal
antimicrobial would have more effect against pathogens and less on the normal
flora of the body. Unfortunately, this is not always possible.
Antimicrobial
drugs are either ---cidal, which means
they actually kill the pathogens, or
----static, which means they slow or prevent
reproduction. In either case, the defenses of the host will also be needed.
1. inhibition of cell wall synthesis—since this
attacks the cell wall, these drugs have little effect on host cells, which do
not contain peptidoglycan. Penicillins, cephalosporins, bacitracin, and
vancomycin act in this way. These work best on gram-positive bacteria.
2. Inhibition of protein synthesis---since
ribosomes of procaryotic cells are slightly different from those of
eucaryocytes, they can be used as a target. Chloramphenicol, erythromycin,
streptomycin, gentamicin, and the tetracyclines act in this way.
3. Injury to the plasma membrane—this is a
mode of action of both some antibacterials and some antifungals. Antifungals
are able to work mostly against fungus cell membranes because they contain
ergosterol instead of cholesterol. However, these antibiotics are potentially
quite toxic to the host. Examples are the polymixins, and antifungals such as amphotericin B,
miconazole, and ketoconazole.
4. Inhibition of nucleic acid synthesis---selective
toxicity varies, but these interfere with DNA replication and transcription.
Rifampin and the quinolones are examples.
5. Inhibiting the synthesis of essential
metabolites---the sulfas and trimethoprim work this way. They interfere
with the pathway by which bacteria synthesize folic acid. Since humans produce
folic acid by a different pathway, these drugs have less effect on human cells.
ANTIBACTERIALS:
Inhibitors
of Cell Wall Synthesis:
Penicillinase-resistant penicillins—not
inactivated by penicillinase—methicillin
Extended-spectrum penicillins—broader spectrum—ampicillin, amosicillin
Penicillins plus β-lactamase
inhibitors—these include clavulanic acid, which prevents damage to
β-lactam ring—augmentin
Cephalosporins—structure & mode
of action similar to penicillins
Bacitracin—polypeptide antibiotic
used only topically
Vancomycin—inhibits peptidoglycan
synthesis—relatively toxic but may be only drug that works against some strains
of Staphylococcus aureus
Antimycobacterial
Antibiotics:
Isoniazid—believed to inhibit synthesis of mycolic acid
Ethambutol—inhibits incorporation
of mycolic acid into cell wall
Inhibitors
of Protein Synthesis:
Chloramphenicol—broad spectrum and can be synthesized chemically (doesn’t have
to be made by a microbe)--used only when absolutely necessary due to potential
for aplastic anemia
Aminoglycosides—streptomycin,
neomycin, gentamicin—may be toxic to auditory nerve or kidneys
Tetracyclines—broad spectrum,
effective against chlamydias & rickettsias—tetracycline, oxytetracycline,
chlortetracycline,doxycycline
Macrolides—erythromycin, clarithromycin—used
to treat infections due to bacteria resistant to penicillins
Streptogramins—developed to combat
resistance to vancomycin—synercid
Oxazolidinones—new synthetic
antibiotics which may be effective abainst MRSA
Polymixin
B—used topically, very effective against gram-negative bacteria
Rifamycins—used
to treat tuberculosis, inhibits synthesis of mRNA—rifampin
Quinolones & Fluoroquinolenes—nalidixic
acid was the first quinolone, Cipro is best known fluoroquinolone
Sulfonamides—sulfa drugs—block synthesis of folic acid, a precursor to
nucleic acids—trimethoprim & sulfamethoxazole in combination
Selective
toxicity is a bigger problem because fungi
are eukaryotic cells. One difference is that they use ergosterol in
place of cholesterol in their plasma membranes, so that is one area that
antifungals can attack. Fungal cell walls are another target. Overall,
antifungals are more toxic to the patient that antibacterials, and some of them
require frequent test to monitor possible liver damage.
Topical antifungals—miconazole,
tolnaftate, undecylenic acid
Systemic antifungals—amphotericin
B, ketoconazole, fluconazole, terbinafine, griseofulvin
Antivirals are few & far between. Since viruses invade cells and use cellular mechanisms for replication of nucleic acid & protein synthesis, selective toxicity is a major problem. There are a few antivirals, and many of these are effective only against retroviruses, the group that includes HIV.
Influenza—amantadine, Tamiflu, Relenza
Herpes—acyclovir, ribovirin
ANTIPROTOZOAL & ANTIHELMINTHIC
Antiprotozoals include quinine, chloroquine, quinacrine, metronidazole
Antihelminthics include niclosamide, praziquantel, mebendazole, alendazole, ivermectin
TABLE 20.3 P. 587 - 590
Although
in many cases chemotherapy is begun by guessing which drug might be effective,
tests to determine effectiveness are sometimes used. This might be necessary
when drug resistance is a problem, or when the patient has not responded to the
first medication.
1. The
Kirby-Bauer diffusion (disk diffusion) method—After inoculating the
trouble-making organism onto an agar plate, discs containing various
antibiotics are applied to the surface and zones of inhibition are observed.
2. The E
test—this determines the minimal inhibitory concentration (MIC). The lower the
concentration that is effective, the better the chance for good results in a
patient. A plastic-coated strip contains a gradient of antibiotic
concentrations and can be read after incubation.
3. Broth
dilution tests---this is another way to determine the minimum inhibitory
concentration that is effective. This involves use of a series of broth
cultures, each containing a different concentration of the antibiotic. Although
more complicated, this test is very accurate and also determines whether the
drug is bacteriostatic or bacteriocidal.
What do bacteria do that makes them resistant
to an antibiotic?
1.
Microbes release an enzyme that modifies or destroys the antibiotic.
Penicillinase is an example of this.
2.
Something about the microbe changes and makes it difficult or impossible for
the antibiotic to penetrate into the bacteria. This often is a change in the
outer membrane.
3. The
microbe develops a way to pump out the antibiotic so fast it does little harm.
Many organisms can pump out tetracyclines, for example.
4.
Microbe develops an alternate chemical reaction to the one the antibiotic
blocks.
5.
Microbe may make a slight change in whatever cell component the antibiotic
attacks.
Many of
these changes are due to random mutations. Once even one microbe becomes
resistant, it passes the resistance on. If only microbes that are resistant
survive, the entire population of microbes soon becomes resistant.
Another
major problem with resistance is that the genes that make an organism resistant
are often carried on a plasmid. The R plasmids are often shared among bacteria,
increasing the resistance problem.
Many
bacterial diseases are now very commonly resistant to antibiotics, and there
are strains of pathogenic bacteria that are resistant to all known antibiotics.