Important words and
concepts from Chapter 13, Black, 1999 (3/28/2003):
by Stephen T. Abedon (abedon.1@osu.edu)
for Micro 509
at the Ohio State University
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Course-external links are
in brackets Click [index] to access site index Click here to access
text’s website Vocabulary
words
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(1) Chapter title: Antimicrobial Therapy
(a)
Antimicrobial
therapy is the treatment of infectious disease
using, typically, chemotherapeutic agents that either kill microbes or otherwise interfere with microbial growth
(b)
"Infectious
disease claimed the lives of about one in every 100 U.S. residents per year as
late as 1900 but only about one in every 300 in 1990. Although antimicrobial agents still don't save all patients, they have
drastically lowered the death rate from infectious disease. A period of
increased infectious diseases could return, however, if patients and the
medical community fail to protect the effectiveness of antimicrobial agents. As
many pathogens develop resistance to available antimicrobial drugs, our ability
to fight infectious diseases is dwindling." (p.
340, Black, 1999)
(c)
[“It is said that the discovery
and use of antibiotics and immunization procedures against infectious disease
are two developments in the field of microbiology that have contributed about
twenty years to the average life span of humans in developed countries where
these practices are employed. While the greater part of this span in time is
probably due to vaccination, most of us are either still alive or have family
members who are still alive because an antibiotic conquered an infectious
disease that otherwise would have killed the individual. If we want to retain
this medical luxury in our society we must be vigilant and proactive: we must
fully understand how and why antimicrobial agents work, and why they don't
work, and realize that we must maintain a stride ahead of microbial pathogens
that can only be contained by antibiotic chemotherapy.” (Microbiology Webbed Out)]
(d)
[“In
1922, Alexander Fleming, a bacteriologist in London, had a cold. He was not one
to waste a moment and consequently used his cold as an opportunity to do an
experiment. He allowed a few drops of his nasal mucus to fall on a culture
plate containing bacteria. He was excited to find some time later that the
bacteria near the mucus had been dissolved away. Fleming showed that the
antibacterial substance was an enzyme, which he named lysozyme—lyso
because of its capacity to lyse bacteria and zyme because it was an
enzyme… Fleming found that tears are a rich source of lysozyme. Volunteers
provided tears after they suffered a few squirts of lemon—an ‘ordeal by lemon.’
The St. Mary’s Hospital Gazette published a cartoon showing children
coming for a few pennies to Fleming’s laboratory, where one attendant
administered beatings while another collected their tears! Fleming was
disappointed to find that lysozyme was not effective against the most harmful bacteria.
But seven years later, he did discover a highly effective antibiotic,
penicillin—a striking illustration of Pasteur’s comment that chance favors a
prepared mind.” (Lubert Stryer, 1995, Biochemistry Fourth Edition, pp.
207-8)]
(e)
[antimicrobial therapy (Google Search)] [Antimicrobial Chemotherapy (complex site with nice
overview of subject)] [therapeutic category index (this is an amazing list of antimicrobials all linked to extensive
descriptions including discussions of mechanisms of action) (Lexi-comp,
Inc. / Emedline)] [index]
(f)
CHEMOTHERAPEUTIC
ANTIMICROBIALS
(2) Chemotherapy (chemotherapeutic agent, drug)
(a)
Chemotherapy
is the use of chemical substances to treat disease
(b)
To
be effective, a chemotherapeutic agent (i.e., a drug) must combat the disease
(e.g., poison a pathogen) to a greater extent than that drug poisons the host
(c)
Symptoms
of host poisoning we call side effects
(d)
[chemotherapy -cancer,
"chemotherapeutic
agent" -cancer (Google Search)] [index]
(a)
An
antimicrobial agent is a chemotherapeutic agent
used to treat the underlying cause of infectious disease,
i.e., by inhibiting microbial growth and microbial survival
(b)
[“Although the immune system
efficiently and regularly protects us from microorganisms intent on upsetting
the balance between themselves and their host, there are times when it cannot
cope, especially when it is confronted with invasion by rapidly growing
microorganisms. In these and other situations, antibiotics which kill
microorganisms or inhibit their growth give the immune system the time it needs
to produce a favourable outcome for the host, avoiding damage and in some cases
potential death of the host.” “Bactericidal agents are
generally more effective than bacteriostatic agents, but bacteriostatic agents
can be extremely beneficial since they provide time for the normal defences of
the host to kill the microorganisms. Knowledge of whether the action of an
antibiotic is bactericidal or bacteriostatic means that the potential outcome
of using combinations of antibiotics can be predicted.” (Antimicrobial Chemotherapy)]
(c)
Antimicrobial
agents come in a variety of types that may be differentiated in terms of
(i)
Modes
of action
(ii)
Source
(e.g., various microbes such as Streptomyces spp.)
(iii)
Mechanism
of production (e.g., antibiotics versus synthetic drugs
versus semisynthetic drugs)
(iv)
Toxicity / side effects
(vi)
Evolved or inherent organismal resistance
(d)
[antimicrobial agent
(Google Search)]
[index]
(a)
An
antibiotic is "a chemical substance produced
by microorganisms which has the capacity to inhibit the growth of bacteria
and even destroy bacteria and other microorganisms in dilute solution."
(emphasis mine) (p. 341, Black, 1999)
(b)
[“Penicillium and Cephalosporium: produce
Beta-lactam antibiotics: penicillin, cephalosporin, and their relatives. ¶
Actinomycetes, mainly Streptomyces species: produce tetracyclines, aminoglycosides
(streptomycin and its relatives), macrolides (erythromycin and its relatives),
chloramphenicol, ivermectin, rifamycins, and most other clinically-useful
antibiotics that are not beta-lactams. ¶ Bacillus species, such as B. polymyxa and Bacillus subtilis produce
polypeptide antibiotics (e.g., polymyxin and bacitracin), and B. cereus produces
zwittermicin. ¶ These organisms all have in common that they live in a soil
habitat and they form some sort of a spore or resting structure. It is not
known why these microorganisms produce antibiotics but it may rest in the
obvious: affording them some nutritional advantage in their habitat by
antagonizing the competition… Antibiotics tend to be rather large, complicated,
organic molecules and may require as many as 30 separate enzymatic steps to
synthesize. The maintenance of a substantial component of the bacterial genome
devoted solely to the synthesis of an antibiotic leads one to the conclusion
that the process (or molecule) is important, if not essential, to the survival
of these organisms in their natural habitat. ¶ Most of the microorganisms that
produce antibiotics are resistant to the action of their own antibiotic,
although the organisms are affected by other antibiotics, and their antibiotic
may be effective against closely-related strains.” (Microbiology Webbed Out)]
(c)
[“In the majority of situations
in which antibiotics are used, a "best guess" procedure is followed.
A doctor makes a provisional diagnosis that a patient has a bacterial infection
which requires treatment. Depending on the type of infection there will be a
short list of bacteria most likely to be causing that infection. Depending on
the type of bacteria there will be an antibiotic most likely to successfully
treat that infection. The doctor is then in the position to write a
prescription for that antibiotic. There are inherent risks in following this
course of action. ¶ "Best
guess" treatment is not always successful or appropriate as many bacteria
have unpredictable susceptibilities to antimicrobial agents. The susceptibilities
or resistances of unusual or hospital acquired causes of infection invariably
need to be determined to help guide the selection of the most appropriate
antimicrobial agent. Alternatively it could be said that the activity of
different antibiotics towards these bacteria (needs) to be determined.”
(Antimicrobial Chemotherapy)]
(d)
[antibiotic (Google Search)] [what the heck is an
antibiotic? (Jack Brown – University of Kansas] [classification of antibiotics,
brief overview of structures
and characteristics of select antibiotics (Antimicrobial Chemotherapy)]
[general characteristics of
antibiotics] [antibiotics (see
Table 4 on this page for a nice summary of antibiotic types, specific examples,
their sources, and their modes of action) (Microbiology Webbed Out)] [index]
(e)
[Fungus-growing ants use
antibiotic-producing bacteria to control garden parasites (an
article published in Nature and presented in its entirety)]
(a)
Contrast
antibiotic
with synthetic drug: Synthetic drugs are substances, some of which can act
identically to antibiotics, but which are synthesized in the laboratory rather
than by a microorganism
(b)
["synthetic drug" and
antibiotic (Google Search)]
[index]
(a)
The
middle ground between a synthetic drug and an antibiotic is an antimicrobial
agent that is produced by chemically modifying a natural product, e.g., the
chemical modification of an antibiotic or its precursor
(b)
[semisynthetic drug
(Google Search)]
[index]
ANTIBIOTIC EFFICACY
(a)
The
ability of an antimicrobial to harm a pathogen without
harming the host is termed selective toxicity
(b)
[“The single most important
characteristic [of an antimicrobial agent] is selective toxicity, meaning that
the antibiotic is far more toxic to the microorganism than to the host. A drug
that disrupts a microbial function not found in eucaryotic animal cells often
has a greater selective toxicity and a higher therapeutic index.” (Antimicrobial Chemotherapy)]
(c)
No
antimicrobial possesses no toxicity at all possible doses
(d)
Instead,
selective toxicity refers to the range between the dose necessary to inhibit
pathogen growth and the dose at which the host is harmed
(e)
We
can quantify selective toxicity in terms of
(i)
The
therapeutic dosage level
(ii)
The
toxic dosage level
(iii)
The
chemotherapeutic index
(f)
[selective toxicity
(Google Search)]
[index]
(a)
This
is the dose at which pathogen growth is inhibited
(b)
Ideally,
at this dosage the antimicrobial is not toxic to the host
(c)
Note
that a number of factors influence whether a therapeutic dosage level may be
established and then maintained at the site of infection (both quotes from p.
663 of Prescott, Harley, and Klein, 1996. Microbiology
Third Edition. Wm C. Brown Publishers):
(i)
“The
drug must actually be able to reach the site of infection. The mode of
administration plays an important role. A drug such as penicillin G is not
suitable for oral administration because it is relatively unstable in stomach
acid. Some antibiotics… are not well absorbed from the intestinal tract and
must be injected intramuscularly or given intravenously… Even when an agent is
administered properly, it may be excluded from the site of infection. For
example, blood clots or necrotic tissue can protect bacteria from a drug,
either because body fluids containing the agent may not easily reach the
pathogens or because the agent is absorbed by materials surrounding it.”
(ii)
“The
chemotherapeutic agent must exceed the pathogen’s MIC (minimum inhibitory
concentration) value if it is going to be effective. The concentration reached
will depend on the amount of drug administered, the route of administration and
speed of uptake, and the rate at which the drug is cleared or eliminated from
the body. It makes sense that a drug will remain at high concentrations longer
if it is absorbed over a long period and excreted slowly.”
(d)
[therapeutic dosage
(Google Search)]
[index]
(a)
This
is the dose at which the host is harmed
(b)
Many
antibiotics
can be toxic (often extremely so) in numerous ways
(c)
See
the discussion of individual antibiotics on pages 355-on in your text as well
as in the following figures (no need to memorize all antibiotics):
(i)
Figure 13.13, Selected
antibacterial drugs
(ii)
Figure 13.15, Selected
antifungal, antihelminthic, antiviral, and antiprotozoan drugs
(d)
[toxic dosage (Google Search)] [index]
(a)
Ideally,
the therapeutic dosage level is significantly lower
than the toxic dosage level
(b)
The
ratio of toxic dosage level to the therapeutic dosage level is termed the chemotherapeutic
index (more specifically: “…the chemotherapeutic index is defined as the
maximum tolerable dose per kilogram of body weight, divided by the minimum dose
per kilogram body weight, that will cure the disease.” p. 342, Black, 1999)
(c)
The
higher this number the better
(d)
Anti-cancer
chemotherapeutics are examples of drugs (though not antimicrobials) that typically have low chemotherapeutic
indices; this is because cancer cells so closely resemble normal body cells
that it is difficult to poison the cancer cells without poisoning the body as
well
(e)
A
broadly useful antibiotic will have a high chemotherapeutic index
(f)
Typically
this is accomplished by the chemotherapeutic drug attacking a pathogen molecule
or metabolic pathway that is not also present in or used by the host
(g)
Note
that drugs with low chemotherapeutic indices when taken internally may still be
acceptable for topical use (e.g., bacitracin)
(h)
Other
drugs with low chemotherapeutic indices are still employed internally because
they represent the only drugs available to treat various infections (e.g.,
vancomycin)
(i)
[chemotherapeutic index
(Google Search)]
[index]
(a)
Not
all antimicrobials inhibit the growth of all
microbial pathogens
(b)
In
fact, not one antimicrobial inhibits the growth of all microbial pathogens
(c)
Instead,
just as viruses have host ranges, antimicrobials have spectrums of activity,
that range of pathogen types a given antimicrobial is active against
(d)
We
can distinguish antimicrobial agents into those that have a broad spectrum of activity and those that have narrower spectrums of activity
(e)
See Figure 13.1, The
spectrum of antibiotic activity
(f)
See Table 13.1, The spectrum
of activity of selected antimicrobial agents
(g)
[spectrum of activity
(Google Search)]
[index]
(12) Broad spectrum of activity
(a)
An
antimicrobial drug that is effective against a large variety of microorganisms
is said to have a broad spectrum of activity
(b)
An
example of an antimicrobial with a broad spectrum of activity would by one that
is effective against both Gram-negative and Gram-positive bacteria
(c)
See Figure 13.1, The
spectrum of antibiotic activity
(d)
Advantages
of using a broad-spectrum antibiotic are a high likelihood of efficacy against
an unidentified pathogen
(e)
[broad spectrum of activity
(Google Search)]
[index]
(13) Normal flora (normal microbiota)
(a)
Disadvantages of using a broad-spectrum antibiotic
are a high likelihood of the drug also destroying the friendly/helpful bacteria
making up an individual's normal microbial flora,
i.e., the non-pathogenic microorganisms normally found associated with a host
(b)
"Because they have such a wide spectrum of activity,
[tetracyclines]
destroy the normal intestinal microflora and often produce severe
gastrointestinal disorders." (p. 360, Black, 1999)
(c)
[normal microflora (MicroDude)]
[index]
(a)
Knocking
out these non-pathogenic bacteria can lead to disease (e.g., diarrhea, Clostridium difficile-associated
colitis, Candida vaginal yeast
infections, etc.)
(b)
Normal
flora can compete with pathogenic bacteria (microbial antagonism), thus
preventing disease; removing these flora can thus make an individual more
susceptible to subsequent disease
(c)
The
replacement of a normal flora member by a pathogen is called superinfection
(d)
This
is particularly a problem in hospital settings due to the common occurrence in
those settings of readily superinfecting pathogens
(e)
A
means of combating superinfection is essentially normal-flora replacement
therapy
(f)
[superinfection, superinfection and antibiotic,
Candida
superinfection, Candida
infection, C. difficile
superinfection, C. difficile colitis
(Google Search)]
[index]
(15) Narrow spectrum of activity
(a)
A
narrow-spectrum antibiotic is effective against only a relatively small subset
of bacteria
(b)
Use
of a narrow-spectrum antibiotic allows an avoidance of some of the destruction
of normal flora associated with antibiotic use
(c)
Penicillin
is an example of an antibiotic possessing a relatively narrow spectrum of
activity, acting particularly against Gram-positive bacteria (i.e., ones with
cell walls but lacking outer membranes)
(d)
Disadvantages
include a requirement before treatment can commence for pathogen identification
and, in some cases, identification of pathogen antibiotic susceptibility
(e)
[narrow spectrum of activity
(Google Search)]
[index]
SPECIFIC ANTIBIOTICS
(16) Modes of action (mechanism of action)
(a)
"Like
other medicines, antimicrobial agents are sometimes used simply because they
work, without our always knowing how they work. Many people's lives have been
saved by medicines whose actions at the cellular level have never been
understood. However, it is always desirable to know the mode of action of an
agent. With that knowledge, effects of actions on patients can be better
monitored and controlled, and ways of improving them may be found." (p.
342, Black, 1999)
(b)
“For an antibiotic to affect
the growth of a microbial cell it must (i) enter the cell and reach the site of
action, (ii) bind to a target molecule involved in an essential cell process,
(iii) markedly inhibit this process. An antibiotic can be bactericidal or
bacteriostatic. A bactericidal effect occurs when the antibiotic interaction
results in an irreversible disruption or binding whereas a bacteriostatic
effect involves lower affinity binding and as such is reversible when the
antibiotic is removed from the environment.” (Antimicrobial Chemotherapy)
(c)
Five
modes of antimicrobial action are discussed by your text:
(i)
Inhibition of cell wall synthesis
(ii)
Disruption of cell membrane function
(iii)
Inhibition of protein synthesis
(iv)
Inhibition of nucleic acid synthesis (i.e.,
inhibition of replication of genetic material or transcription)
(d)
See Figure 13.2, Modes of
action