Module 5
Antimicrobial Treatment and Interactions
Antimicrobial Treatment
A hundred years ago in the United States, one out of three children was expected to die of
an infectious disease before the age of 5. Early death or severe lifelong debilitation from scarlet
fever, diphtheria, tuberculosis, meningitis, and many other bacterial diseases was a fearsome yet
undeniable fact of life to most of the world’s population. The introduction of modern drugs to
control infections in the 1940s was a medical revolution that has added significantly to the life
span and health of humans. It is no wonder that, for many years, antibiotics were regarded as
miracle drugs. But even though antimicrobial drugs have greatly reduced the incidence of certain
infections, they have definitely not eradicated infectious disease and probably never will. In fact,
we are dangerously close to a postantibiotic era, where the drugs we have are no longer effective.
The goal of antimicrobial chemotherapy is deceptively simple: Administer a drug to an
infected person, which destroys the infective agent without harming the host’s cells. In actuality,
this goal is rather difficult to achieve because many (often contradictory) factors must be taken
into account. The ideal drug should be easy to administer, yet be able to reach the infectious
agent anywhere in the body. It should also be toxic to the infectious agent, while being nontoxic
to the host. It should remain active in the body as long as needed, yet be safely and easily broken
down and excreted. Additionally, microbes in biofilms often require different drugs than when
they are not in biofilms. In short, the perfect drug does not exist—but by balancing drug
characteristics against one another, a satisfactory compromise can often be achieved
Identification of infectious agents from body specimens should be attempted as soon as
possible. It is especially important that such specimens be taken before any antimicrobial drug is
given, before the drug reduces the numbers of the infectious agent. Direct examination of body
fluids, sputum, or stool is a rapid initial method for detecting and perhaps even identifying
bacteria or fungi. A doctor often begins the therapy on the basis of such immediate findings, or
even on the basis of an informed best guess. For instance, if a sore throat appears to be caused by
Streptococcus pyogenes, the physician might prescribe penicillin because this species seems to
be almost universally sensitive to it so far. If the infectious agent is not or cannot be isolated,
epidemiological statistics may be required to predict the most likely agent in a given infection.
For example, Streptococcus pneumoniae accounts for the majority of cases of bacterial
meningitis in children, followed by Neisseria meningitidis (discussed in detail in chapter 17).
Identification of infectious agents from body specimens should be attempted as soon as
possible. It is especially important that such specimens be taken before any antimicrobial drug is
given, before the drug reduces the numbers of the infectious agent. Direct examination of body
fluids, sputum, or stool is a rapid initial method for detecting and perhaps even identifying
bacteria or fungi. A doctor often begins the therapy on the basis of such immediate findings, or
even on the basis of an informed best guess. For instance, if a sore throat appears to be caused by
Streptococcus pyogenes, the physician might prescribe penicillin because this species seems to
be almost universally sensitive to it so far. If the infectious agent is not or cannot be isolated,
epidemiological statistics may be required to predict the most likely agent in a given infection.
For example, Streptococcus pneumoniae accounts for the majority of cases of bacterial
meningitis in children, followed by Neisseria meningitidis (discussed in detail in chapter 17).
More sensitive and quantitative results can be obtained with tube dilution tests. First, the
antimicrobial is diluted serially in tubes of broth (often miniaturized tubes called wells in 96-well
plates). Then each tube is inoculated with a small uniform sample of pure culture, incubated, and
examined for growth (turbidity). The smallest concentration (highest dilution) of drug that
visibly inhibits growth is called the minimum inhibitory concentration, or MIC. The MIC is
useful in determining the smallest effective dosage of a drug and in providing a comparative
index against other antimicrobials (figure 10.3). In many clinical laboratories, these antimicrobial
testing procedures are performed in automated machines that can test dozens of drugs
simultaneously.
The physician must also take a careful history of the patient to discover any preexisting
medical conditions that will influence the activity of the drug or the response of the patient. A
history of allergy to a certain class of drugs precludes the use of that drug and any drugs related
to it. Underlying liver or kidney disease will ordinarily require changing the drug therapy
because these organs play such an important part in metabolizing or excreting the drug. Infants,
the elderly, and pregnant women require special precautions. For example, age can diminish
gastrointestinal absorption and organ function, and most antimicrobial drugs cross the placenta
and could affect fetal development. Patients must be asked about other drugs they are taking
because incompatibilities can result in increased toxicity or failure of one or more of the drugs.
This includes over-the-counter drugs and dietary supplements. For example, the combination of
aminoglycosides and cephalosporins can be toxic to kidneys; antacids reduce the absorption of
isoniazid; and the interaction of tetracycline or rifampin with oral contraceptives can abolish the
contraceptive’s effect. Some drug combinations (penicillin with certain aminoglycosides, or
amphotericin B with flucytosine) act synergistically, so that reduced doses of each can be used in
combined therapy
Even when all the information is in, the final choice of a drug is not always easy or
straightforward. Consider the hypothetical case of an elderly alcoholic patient with pneumonia
caused by Klebsiella and complicated by diminished liver and kidney function. All drugs must
be given by injection because of prior damage to the gastrointestinal lining and poor absorption.
Drug tests show that the infectious agent is sensitive to third-generation cephalosporins,
gentamicin, imipenem, and azlocillin. The patient’s history shows previous allergy to the
penicillins, so these would be ruled out. Drug interactions occur between alcohol and the
cephalosporins, which are also associated with serious bleeding in elderly patients, so this may
not be a good choice. Aminoglycosides such as gentamicin are toxic to the kidneys and poorly
cleared by damaged kidneys.
Imipenem causes intestinal discomfort, but it has less toxicity and would be a viable
choice. In the case of a cancer patient with severe systemic Candida infection, there will be fewer
criteria to weigh. Intravenous antifungals are the only possible choices, despite drug toxicity and
other possible adverse side effects. Adding to the complexity of choosing an antimicrobial is our
new knowledge of the human microbiome, especially in the gut. Oral antimicrobials are
chemically modified by the microbes in the gut, in different ways depending on which microbes
are there. This accounts for substantial variability in how different humans respond to the drugs,
and is an active area of research.
The goal of antimicrobial drugs is either to disrupt the cell processes or structures of
bacteria, fungi, and protozoa or to inhibit virus replication. Many antimicrobial drugs interfere
with the function of enzymes required to synthesize or assemble macromolecules, or they destroy
structures already formed in the cell. Above all, drugs should be selectively toxic, which means
they should kill or inhibit microbial cells without simultaneously damaging host tissues. This
concept of selective toxicity is central to antibiotic treatment, and the best drugs in current use
are those that block the actions or synthesis of molecules in microorganisms but not in vertebrate
cells. Examples of drugs with excellent selective toxicity are those that block the synthesis of the
cell wall in bacteria (e.g., penicillins). They have low toxicity and few direct effects on human
cells because human cells lack the chemical peptidoglycan and are thus unaffected by this action
of the antibiotic. Among the most toxic to human cells are drugs that act upon a structure
common to both the infective agent and the host cell, such as the cytoplasmic membrane (e.g.,
amphotericin B, used to treat fungal infections). As the characteristics of the infectious agent
become more and more similar to those of the host cell, selective toxicity becomes more difficult
to achieve, and undesirable side effects are more likely to occur
Because penicillin is such a familiar antibiotic, and because the alterations in the
molecule over the years illustrate how antibiotics are developed and improved upon, we provide
an overview in table 10.6. Here you will see that original penicillin was narrow-spectrum and
susceptible to microbial counterattacks. Later penicillins were developed to overcome those two
limitations. Unfortunately, we don’t seem to be getting it right often enough. A 2016 study by
the Centers for Disease Control and Prevention (CDC) and the Pew Charitable Trust looked at
the three most common infections in the United States: sinus infections, sore throats, and ear
infections. The study found that 48% of these patients were not prescribed the antibiotics
recommended by national standards for these infections. While we just discussed reasons the
first-line antibiotic might not be prescribed, experts say that only about 20% of patients are likely
to have reasons the first-line drug should not be used. Many times the nonrecommended
antibiotics are more broad-spectrum than the recommended ones, and are therefore more likely
to lead to microbiome disruption and increased antibiotic resistance.
As you read in chapter 6, biofilm inhabitants behave differently than their free-living
counterparts. One of the major ways they differ—at least from a medical perspective—is that
they are often unaffected by the same antimicrobials that work against them when they are free-
living. When this was first recognized, it was assumed that it was a problem of penetration, that
the (often ionically charged) antimicrobial drugs could not penetrate the sticky extracellular
material surrounding biofilm organisms. While that is a factor, there is something more
important contributing to biofilm resistance: the different phenotype expressed by biofilm
bacteria. When secured to surfaces, they express different genes and therefore have different
antibiotic susceptibility profiles. Years of research have so far not yielded an obvious solution to
this problem, though there are several partially successful strategies. One of these involves
interrupting the quorum-sensing pathways that mediate communication between cells and may
change phenotypic expression. Daptomycin (trade name: Cubicin), a lipopeptide that is effective
in deep tissue infections with resistant bacteria, has also shown some success in biofilm infection
treatment. Also, some researchers have found that adding DNase to their antibiotics can help
with penetration of the antibiotic through the extracellular debris—apparently some of which is
DNA from lysed cells.
Many biofilm infections can be found on biomaterials inserted in the body, such as
cardiac or urinary catheters. These can be impregnated with antibiotics prior to insertion to
prevent colonization. This, of course, cannot be done with biofilm infections of natural tissues,
such as the prostate or middle ear. Interestingly, it appears that chemotherapy with some
antibiotics—notably aminoglycosides—can cause bacteria to form biofilms at a higher rate than
they o
Because the cells of fungi are eukaryotic, they present special problems in drug
treatment. For one, the great majority of antimicrobial drugs are designed to act on bacteria and
are generally ineffective in combating fungal infections. For another, the similarities between
fungal and human cells often mean that drugs toxic to fungal cells are also capable of harming
human tissues. A few agents with special antifungal properties have been developed for treating
systemic and superficial fungal infections. Four main drug groups currently in use are the
macrolide polyene antibiotics, the azoles, the echinocandins, and allylamines.
Albendazole is a broad-spectrum antiparasitic drug used for several types of roundworm
intestinal infestations. This drug works locally in the intestine to inhibit the function of the
microtubules of worms, eggs, and larvae. This means the parasites can no longer utilize glucose,
which leads to their demise. The compound pyrantel paralyzes the muscles of intestinal
roundworms. Consequently, the worms are unable to maintain their grip on the intestinal wall
and are expelled along with the feces by the normal peristaltic action of the bowel. Two newer
antihelminthic drugs are praziquantel, a treatment for various tapeworm and fluke infections, and
ivermectin, used for strongyloidiasis and onchocerciasis in humans. Helminthic diseases are
described in chapter 20 because these organisms spend a large part of their life cycles in the
digestive tract.
The treatment of viral infections presents unique problems. With a virus, we are dealing
with an infectious agent that relies upon the host cell for the vast majority of its metabolic
functions. With currently used drugs, disrupting viral metabolism requires that we disrupt the
metabolism of the host cell to a much greater extent than is desirable. Put another way, selective
toxicity with regard to viral infection is difficult to achieve because a single metabolic system is
responsible for the well-being of both virus and host. Although viral diseases such as measles,
mumps, and hepatitis are routinely prevented by the use of effective vaccinations, epidemics of
AIDS, influenza, and even the “commonness” of the common cold attest to the need for more
effective medications for the treatment of viral pathogens. The currently used antivir
Antimicrobial Resistance
One unfortunate outcome of the use of antimicrobials is the development of microbial
drug resistance, an adaptive response in which microorganisms begin to tolerate an amount of
drug that would ordinarily be inhibitory. The ability to escape the effects of antimicrobial drugs
is due to the genetic versatility and adaptability of microbial populations. The property of drug
resistance can be intrinsic as well. Resistance is called intrinsic when it is a fixed trait of a
microbe. For example, all microbes are intrinsically resistant to antibiotics they themselves
produce. Of much greater importance is the acquisition of resistance to a drug by a microbe that
was previously sensitive to the drug. In our context, the term antibiotic resistance will refer to
this last type of acquired resistance.
Contrary to popular belief, antibiotic resistance is an ancient phenomenon. Because most
of our oldest therapeutically used antibiotics are natural products from fungi and bacteria,
resistance to them has been a survival strategy for other microbes for as long as the microbes
have been around. The scope of the problem in terms of using the antibiotics as treatments for
humans became apparent in the 1980s and 1990s, when scientists and physicians witnessed
treatment failures on a large scale. The acquisition of drug resistance is not always a result of
exposure to the drug. This adds another dimension to the efforts to prolong antibiotic
effectiveness, which so far have focused on limiting the amount of antibiotic in the environment.
We see now that this is important but not enough to prevent microorganisms from developing
resistance altogether.
There may be a third mechanism of acquiring resistance to a drug, which is a phenotypic,
not a genotypic, adaptation. Recent studies suggest that bacteria can “go to sleep” when exposed
to antibiotics, meaning they will slow or stop their metabolism so that they cannot be harmed by
the antibiotic. They can then rev back up after the antibiotic concentration decreases. Sometimes
these bacteria are called “persisters.” (This is one reason biofilm bacteria are less susceptible to
antibiotics than free-living bacteria are.) Also, some fungi have an additional option for
becoming antibiotic-resistant, as discovered in 2014. In these species of fungi, a small regulatory
RNA known as interfering RNA—or RNAi—has been found to bind to a genetic sequence
temporarily. When it is bound, the gene is silenced and the target of the antibiotic is not
manufactured by the fungus, thus rendering it temporarily resistant to that drug. This provides
the fungus more flexibility, allowing it to express the gene later when the antibiotic is no longer
present. This reversible mechanism is called an epigenetic event, and the gene silencing is called
an epimutation. In the next sections, we will focus on the two genetic changes that can result in
acquired resistance.
Resistance occurring through horizontal transfer originates from plasmids called
resistance (R) factors that are transferred through conjugation, transformation, or transduction.
Such traits are “lying in wait” for an opportunity to be expressed and to confer adaptability on
the species. Many bacteria also maintain transposable drug resistance sequences (transposons)
that are duplicated and inserted from one plasmid to another or from a plasmid to the
chromosome. Chromosomal genes and plasmids containing codes for drug resistance are often
faithfully replicated and inherited by all subsequent progeny. This sharing of resistance genes
accounts for the rapid proliferation of drugresistant species. As you have read in earlier chapters,
gene transfers are extremely frequent in nature, with genes coming from totally unrelated
bacteria, viruses, and other organisms living in the body’s normal biota and the environment.
So far, we have been considering drug resistance at the cellular and molecular levels, but
its full impact is felt only if this resistance occurs throughout the cell population. Let us examine
how this might happen and its long-term therapeutic consequences. Any large population of
microbes is likely to contain a few individual cells that are already drug resistant because of prior
mutations or transfer of plasmids (figure 10.5). While we now know that many things can cause
these “odd balls” to start overtaking the population, one of the most reliable ways to make this
happen is for the correct antibiotic to be present. Individuals that are sensitive to the antibiotic
are inhibited or destroyed, and resistant individuals survive and proliferate. During the
population growth that follows, offspring of these resistant microbes will inherit this drug
resistance. In time, the replacement population will have a preponderance of the drug-resistant
forms and can eventually become completely resistant (figure 10.5). In ecological terms, the
environmental factor (in this case, the drug) has put selection pressure on the population,
allowing the more “fit” microbe (the drug- resistant one) to survive, and the whole population
has evolved to a condition of drug resistance.
Textbooks generally avoid using superlatives and exclamation points. But the danger of
antibiotic resistance can hardly be overstated. The CDC issued a “Threat Report” about this issue
for the first time in 2013, and they continue to monitor the situation, which they label
“potentially catastrophic.” Now it is such a large problem that an economist recently predicted
that worldwide deaths from antibiotic-resistant microbes will surpass deaths from cancer by
2050. This crisis has the world’s attention. In September 2016 a meeting of the General
Assembly of the United Nations was held on this topic, only the fourth time in history a health
issue was the topic of such a meeting. (The other issues were HIV, Ebola, and noncommunicable
diseases.)
New and effective antibiotics have been slow to come to market. There are a variety of
reasons for this, including the economic reality that antibiotics (taken in short courses) are not as
lucrative for drug manufacturers as drugs for chronic diseases, which must often be taken for
life, even though they are just as time-consuming and expensive to develop. Policy makers are
starting to create incentives for the discovery and manufacture of new antibiotics. The CDC has
categorized resistant bacteria into three groups, termed “hazard levels.” The three hazard levels
are concerning, serious, and urgent.
Sometimes the low-tech solution can be the best one. Before antibiotics were discovered
and developed in the 1930s and 1940s, scientists in the former Soviet Union and other regions
were treating patients with mixtures of bacteriophages, whose host bacterium was presumed to
be causing the illness. The antibiotic era put a temporary end to serious consideration of this
strategy, but it is receiving renewed attention as we search for alternatives to antibiotics. One
recent human trial used a mixture of bacteriophages specific for Pseudomonas aeruginosa to treat
ear infections caused by the bacterium.
These infections are found in the form of biofilms and have been extremely difficult to
treat. The phage preparation called Biophage-PA successfully treated patients who had
experienced long-term antibiotic-resistant infections. Other researchers are incorporating phages
into wound dressings. One clear advantage to bacteriophage treatments is the extreme specificity
of the phages— only one species of bacterium is affected, leaving the normal inhabitants of the
body, and the body itself, alone. Phage treatments are currently licensed to decontaminate food
and food-processing facilities, as well as to treat poultry for Salmonella.
Other novel approaches to controlling infections include the use of probiotics and
prebiotics. Probiotics are preparations of live microorganisms that are fed to animals and humans
to improve the intestinal biota. This can serve to replace microbes lost during antimicrobial
therapy or simply to augment the biota that is already there. This is a slightly more sophisticated
application of methods that have long been used in an empiric fashion, for instance, by people
who consume yogurt because of the beneficial microbes it contains. Recent years have seen a
huge increase in the numbers of probiotic products sold in ordinary grocery stores (figure 10.6).
Experts generally find these products safe, and in some cases they can be effective. Probiotics
are thought to be useful for the management of food allergies. Their role in the stimulation of
mucosal immunity is also being investigated.
Interactions between Drug and Host
It is estimated that at least 5% of all persons taking an antimicrobial drug experience
some type of serious adverse reaction to it. The major side effects of drugs fall into one of three
categories: direct damage to tissues through toxicity, allergic reactions, and disruption in the
balance of normal microbial biota. The damage incurred by antimicrobial drugs can be short
term and reversible or permanent, and it ranges in severity from cosmetic to lethal.
One of the most frequent drug reactions is allergy. This reaction occurs because the drug
acts as an antigen (a foreign material capable of stimulating the immune system) and stimulates
an allergic response. This response can be provoked by the intact drug molecule or by substances
that develop from the body’s metabolic alteration of the drug. In the case of penicillin, for
instance, it is not the penicillin molecule itself that causes the allergic response but a product,
benzylpenicilloyl. Allergic reactions have been reported for every major type of antimicrobial
drug, but the penicillins account for the greatest number of antimicrobial allergies, followed by
the sulfonamides. People who are allergic to a drug become sensitized to it during the first
contact, usually without symptoms. Once the immune system is sensitized, a second (or later)
exposure to the drug can lead to a reaction such as a skin rash (hives), respiratory inflammation,
and, rarely, anaphylaxis, an acute, overwhelming allergic response that develops rapidly and can
be fatal.
Most normal, healthy body surfaces, such as the skin, large intestine, outer openings of
the urogenital tract, and oral cavity, provide numerous habitats for a virtual “garden” of
microorganisms. These normal colonists, or residents, called the biota, or microbiota, consist
mostly of harmless or beneficial bacteria, but a small number can potentially be pathogens.
Although we defer a more detailed discussion of this topic to chapter 11 and later chapters, here
we focus on the general effects of drugs on this population. If a broad-spectrum antimicrobial is
introduced into a host to treat an infection, it will destroy “good” microbes as well as the disease-
causing microbe. When this therapy destroys beneficial resident species, other microbes that
were once in small numbers can begin to overgrow and cause disease. This complication is
called a superinfection
Some common examples demonstrate how a disturbance in microbial biota leads to
replacement biota and superinfection. A broad-spectrum cephalosporin used to treat a urinary
tract infection by Escherichia coli will cure the infection, but it will also destroy the lactobacilli
in the vagina that normally maintain a protective acidic environment there. The drug has no
effect, however, on Candida albicans, a yeast that also resides in normal vaginas. Released from
the inhibitory environment provided by lactobacilli, the yeasts proliferate and cause symptoms.
Candida can cause similar superinfections of the oropharynx (thrush) and the large intestine. Oral
therapy with some antimicrobials is associated with a serious and potentially fatal condition
known as antibiotic-associated colitis (pseudomembranous colitis). This condition is caused by
the overgrowth of the endospore-forming bacterium Clostridioides difficile. It invades the
intestinal lining and releases toxins that induce diarrhea, fever, and abdominal pain. It has
become an urgent public health problem, as you read earlier.
Tons of antimicrobial drugs produced in this country are exported to other countries,
where controls are not as strict. Nearly 200 different antibiotics are sold over the counter in Latin
America and Asian countries. It is common for people in these countries to self-medicate without
understanding the correct medical indication. Drugs used in this way are not only likely to be
ineffective, but, worse yet, they are known to be responsible for emergence of drug-resistant
bacteria that subsequently cause epidemics. On top of that, about 140,000 tons of antibiotics are
used at low levels in livestock around the world in order to enhance their growth. As you know,
low levels of antibiotics used for the long term are the best conditions for creating antibiotic-
resistant bacteria. They can then transfer into human beings. In 2017, the U.S. Food and Drug
Administration banned the use of medically important antibiotics for the use of growth
promotion in livestock.
Interactions between Microbes and Humans
It is easy to think of humans and other mammals as discrete, stand-alone organisms that
are also colonized by some nice, no harmful microorganisms. In fact, that’s what scientists
thought for the last 150 years or so. But the truer picture is that humans and other mammals have
the form and the physiology that they have due to having been formed in intimate contact with
their microbes. Do you see the difference? The human microbiome, the sum total of all microbes
found on and in a normal human, is critically important to the health and functioning of its host
organism. This chapter describes the relationship between the human and microorganisms, both
the good (the majority) and the bad.
Our bodies consist of more microbial cells than human cells. Some microbes are colonists
(normal biota), some are rapidly lost (transients), and others invade the tissues. Sometimes
resident biota become invaders. For the most part our resident microbiota, the human
microbiome, colonize us for the long term, and do not cause disease. We encounter transient
microbes in our environment, most of which are harmless, although occasionally they lead to
infection, a condition in which microbes get past the host defenses, enter the tissues, and
multiply. We may or may not be aware that an infection is taking place. When the cumulative
effects of the infection damage or disrupt tissues and organs, the pathologic state that results is
disease. A disease is defined as any deviation from health. There are hundreds of different
human diseases, caused by such factors as infections, genetics, aging, and malfunctions of
systems or organs. In this chapter we discuss only infectious disease—a pathologic state caused
directly by microorganisms or their products. When you consider the evolutionary time line
(refer to figure 1.2) of bacteria and humans, it is quite clear that humans evolved in an
environment that had long been populated by bacteria and single-celled eukaryotes. It should not
be surprising, therefore, that humans actually require the microbes in and on their bodies for
proper growth and development.
The extent to which this is true has been surprising even to the scientists studying it.
Since 2007, a worldwide research effort has been underway that utilizes the powerful techniques
of genome sequencing and “big data” tools. The American effort is called the Human
Microbiome Project (HMP), and there are similar projects occurring around the world. The aim
has been not only to characterize the microbes living on human bodies when they are healthy but
also to determine how the microbiome differs in various diseases. Previous to this international
project, scientists and clinicians mainly relied on culture techniques to determine what the
“normal biota” consisted of. That meant we only knew about bacteria and fungi that we could
grow in the laboratory, which vastly undercounts the actual number and variety because many—
even the majority of—microbes cannot be cultured in the laboratory, though they grow quite
happily on human tissues.
Microbiome research has shown that among healthy adults, the normal microbiota varies
significantly. For instance, the microbiota on a person’s right hand was found to be significantly
different than that on the same person’s left hand. What seemed to be more important than the
exact microbial profile of any given body site was the profile of proteins, especially the
enzymatic capabilities. That profile remained stable across subjects, though the microbes that
were supplying those enzymes could differ broadly. Scientists are in the process of cataloging
other microorganisms besides bacteria via metagenomics—and just beginning to appreciate their
numbers in the human microbiome. The information about the human microbiome presented in
this chapter reflects new findings. We will try to show you the differences between the old
picture of normal biota in various organ systems and the new, emerging picture. At this point in
medical history, it will be important to appreciate the transitioning view.
The human body offers a seemingly endless variety of environmental niches, with wide
variations in temperature, pH, nutrients, and oxygen tension occurring from one area to another.
Because the body provides such a range of habitats, it should not be surprising that the body
supports a wide range of microbes. Table 11.1 provides a breakdown of our current
understanding of the microbiota living in and on a healthy host. The uppermost row contains the
set of sites that microbiologists have long known to host a normal biota. The middle row presents
some new sites recently found to harbor microbiota in a healthy human. The bottom row reports
that two sites, the brain and the bloodstream, have both been found to contain DNA from
multiple species of bacteria. Their exact role there is not entirely clear yet.
The generally antagonistic effect “good” microbes have against intruder microorganisms
is called microbial antagonism. Normal biota exist in a steady established relationship with the
host and are unlikely to be displaced by incoming microbes. This antagonistic protection is partly
the result of a limited number of attachment sites in the host site, all of which are stably occupied
by normal biota. This antagonism is also enabled by the chemical or physiological environment
created by the resident biota, which is hostile to most other microbes. There are often members
of the “normal” biota that would cause disease if they were allowed to multiply to larger
numbers. Microbial antagonism is also responsible for keeping them in check.
Until rather recently, the uterus and its contents were thought to be sterile during
embryonic and fetal development and remain essentially germ-free until just before birth (figure
11.1). We now know that the placenta harbors a small but significant array of bacteria. The next
important source of microbiota for a newborn is its trip through the vagina. The vaginas of
healthy women of child-bearing age contain a variety of bacteria. They are especially rich in
Lactobacillus bacteria, which are capable of digesting milk, and in other species that have been
found useful in protecting the baby from skin disorders and other conditions. Of course, in the
United States about 30% of babies are born by cesarean section (either through medical necessity
or as elective procedures). Studies have shown that babies born this way have different gut
microbiomes than those born vaginally, at least initially. There is a lot of research examining the
long-term effects of this difference. Some people advocate for swabbing the newborn baby with
gauze containing the mother’s vaginal fluids, but there is still no evidence that this produces a
long-term benefit. So far there are more questions than answers about the difference in
microbiomes resulting from C-sections and vaginal births.
The baby continues to acquire resident microbiota from the environment, notably from its
diet. Throughout most of evolutionary history, of course, that means human breast milk.
Scientists have found that human milk contains around 600 species of bacteria and a lot of sugars
that babies cannot digest. The sugars are used by healthy gut bacteria, suggesting a role for breast
milk in maintaining a healthy gut microbiome in the baby. The skin, gastrointestinal tract, and
portions of the respiratory and genitourinary tracts all continue to be colonized as contact
continues with family members, health care personnel, the environment, and food.
When Colonization Leads to Disease
A microbe whose relationship with its host is parasitic and results in infection and disease
is termed a pathogen. Various aspects of the host influence whether a microbe will have severe,
mild, or no effects. Variation in the genes coding for components of the immune system—or
even the anatomy of infection sites—is one of these factors. Gender, hormone levels, and overall
health also play a role. Pathogenicity, then, is a broad concept that describes an organism’s
potential to cause disease and is used to divide pathogenic microbes into one of two groups. True
pathogens (primary pathogens) are capable of causing disease in healthy persons with normal
immune defenses. They are generally associated with a specific, recognizable disease, which
may vary in severity from mild (colds) to severe (malarial) to fatal (rabies). Examples of true
pathogens include the influenza virus, plague bacillus, and malarial protozoan.
Opportunistic pathogens cause disease when the host’s defenses are compromised or
when the pathogens become established in a part of the body that is not natural to them.
Opportunists are not considered pathogenic to a normal healthy person and, unlike true
pathogens, do not generally possess well-developed virulence properties. Examples of
opportunistic pathogens include Pseudomonas species and Candida albicans. In practice, the
distinction between true pathogens and opportunistic pathogens is becoming less useful as we
gain more understanding of the many factors controlling the disease process. We’ll discuss this
more later. The relative severity of the disease caused by a particular microorganism depends on
the virulence of the microbe. Although the terms pathogenicity and virulence are often used
interchangeably, virulence is the accurate term for describing the degree of pathogenicity.
There is much involved in both of these steps. To establish themselves in a host,
microbes must enter the host, attach firmly to host tissues, negotiate the microbiome, and survive
the host defenses. To cause damage, microbes produce toxins or induce a host response that is
actually injurious to the host. Any characteristic or structure of the microbe that contributes to
the preceding activities is called a virulence factor. Virulence can be due to single or multiple
factors. In some microbes, the sources of virulence are clearly established, but in others they are
not.
From the very earliest days of infectious disease studies, in the 1800s, scientists isolated
single microorganisms to study their effects on animals or humans. Later in this chapter you will
learn about Koch’s postulates, a set of rules for determining the cause of an unknown infectious
condition. The postulates depend on obtaining microbes in pure culture. This procedure is
extremely valuable because, as you know, most scientific experimentation requires isolating the
variables and holding all but one constant. This aspect of scientific rigor has probably kept us
from understanding the roles that interacting microbes play in causing disease. Many scientists
now believe that the majority of infections are polymicrobial, with contributions from more than
one microbe. One classic set of infections is influenza (caused by a virus) and pneumonia (often
caused by a bacterium). Influenza infection frequently leads to pneumonia. In another example,
several types of skin infections are known to be caused by either Staphylococcus or
Streptococcus species. In fact, researchers have found that when these two are cultivated together
with another common skin resident, Moraxella, both staph and strep increase their transcription
of virulence factors. Perhaps upon diagnosis one or the other is isolated from the skin, but it
seems possible that the three of them together led to the disease symptoms.
Another factor crucial to the course of an infection is the quantity of microbes in the
inoculating dose. For most agents, infection will proceed only if a minimum number, called the
infectious dose (ID), is present. This number has been determined experimentally for many
microbes. On the low end of the scale, the ID for Coxiella burnetii, the causative agent of Q
fever, is only a single cell, and the ID is only about 10 infectious cells in tuberculosis, giardiasis,
and coccidioidomycosis. The ID is 1,000 bacteria for gonorrhea and 10,000 bacteria for typhoid
fever, in contrast to 1,000,000,000 bacteria in cholera. Numbers below an infectious dose will
generally not result in an infection. But if the quantity is far in excess of the ID, the onset of
disease can be extremely rapid.
Adhesion is a process by which microbes gain a more stable foothold on host tissues.
Because adhesion is dependent on binding between specific molecules on both the host and
pathogen, a particular pathogen is limited to only those cells (and organisms) to which it can
bind. Once attached, the pathogen is poised advantageously to invade the body compartments.
Bacterial, fungal, and protozoal pathogens attach most often by mechanisms such as fimbriae
(pili), surface proteins, and adhesive slimes or capsules. Viruses attach by means of specialized
receptors. In addition, parasitic worms are mechanically fastened to the portal of entry by
suckers, hooks, and barbs. There are many different methods in which microbes can attach
themselves to host tissues. Firm attachment to host tissues is almost always a prerequisite for
causing disease because the body has so many mechanisms for flushing microbes and foreign
materials from its tissues
Microbes that are not established in a normal biota relationship in a particular body site in
a host are likely to encounter resistance from host defenses when first entering, especially from
certain white blood cells called phagocytes. These cells ordinarily engulf and destroy pathogens
by means of enzymes and antimicrobial chemicals (see chapter 12). Antiphagocytic factors are
used by some pathogens to avoid phagocytes. The antiphagocytic factors of microorganisms help
them to circumvent some part of the phagocytic process (see figure 11.2b). The most aggressive
strategy involves bacteria that kill phagocytes outright. Species of both Streptococcus and
Staphylococcus produce leukocidins, substances that are toxic to white blood cells. Some
microorganisms secrete an extracellular surface layer (slime or capsule) that makes it physically
difficult for the phagocyte to engulf them. Streptococcus pneumoniae, Salmonella typhi,
Neisseria meningitidis, and Cryptococcus neoformans are notable examples. Some bacteria are
well adapted to survive inside phagocytes after ingestion. For instance, pathogenic species of
Legionella, Mycobacterium, and many rickettsias are readily engulfed but are capable of
avoiding destruction. The ability to survive intracellularly in phagocytes has special significance
because it provides a place for the microbes to hide, grow, and be spread throughout the body.
A toxin is a specific chemical product of microbes that is poisonous to other organisms.
A toxin is named according to its specific target of action: Neurotoxins act on the nervous
system; enterotoxins act on the intestine; hemotoxins lyse red blood cells; and nephrotoxins
damage the kidneys. There are two broad categories of bacterial toxins. Exotoxins are proteins
with a strong specificity for a target cell and extremely powerful, sometimes deadly, effects.
They generally affect cells by damaging the cell membrane and causing lysis or by disrupting
intracellular function. Hemolysins (hee-mahl′-uh-sinz) are a class of bacterial exotoxin that
disrupts the cell membrane of red blood cells (and some other cells, too). This damage causes the
red blood cells to hemolyze—to burst and release hemoglobin pigment. Hemolysins that increase
pathogenicity include the streptolysins of Streptococcus pyogenes and the alpha (α) and beta (β)
toxins of Staphylococcus aureus. When colonies of bacteria growing on blood agar produce
hemolysin, distinct zones appear around the colony. The pattern of hemolysis is often used to
identify bacteria and determine their degree of virulence
This mechanism that microbes use to damage host cells is the most recently discovered.
Microbes have been shown to shut down or activate regions of DNA in the host cell, via
epigenetic processes. They can include binding to host cell histones, binding to the small RNAs
used for the silencing of genes, binding to chromatin itself, and so forth. These changes can harm
the host cell, or change its function in some way that favors persistence of the microbe in or on
it. Some pathogens have been found to secrete proteins that interact with regions of host cell
DNA that are responsible for cytoskeleton structure, and thereby cause disorganization of the
cell. Sometimes these changes are passed on to new host cells, causing persistent symptoms.
Some researchers speculate that this could be one source of unexplained illnesses or symptoms
where no causative microbes are found.
Now that you have studied what it takes for a microbe to cause disease, we can put that in
perspective with respect to a particular human host. In previous times, microbes were assigned to
categories such as pathogen or nonpathogen. It is true that some microbes are very likely to
cause disease (the rabies virus), and other microbes are unlikely to cause disease (Lactobacillus
bacteria in our gut). But most microbes fall somewhere in between, meaning they can cause
disease under the right circumstances. In addition, the other part of the disease equation is the
human host. There are many variables among humans, both more or less permanent (genetics)
and temporary (fatigue or pregnancy) characteristics. When there is a decrease in a host’s ability
to mount an immune defense, these patients are termed immunocompromised. This situation can
come about due to an underlying condition (that is, pregnancy or an autoimmune disease) or due
to drugs being taken for another disease, such as cancer. Because of advances in treatment of
many chronic diseases and cancer, many more people who are functioning in daily society are, in
fact, immunocompromised. This makes them more susceptible to infections.
Microbes that don’t usually cause disease in healthy people are called opportunistic
pathogens. These are microbes that take advantage of immunocompromised hosts to cause
disease. It is more useful to assess each host-microbe encounter on its own terms. In every
encounter between a microbe and a host, several factors determine whether disease will result. It
is why you may be the only member of your family not sickened by that “bad” potato salad that
everyone ate, for example. Figure 11.5 lays out the factors on both sides—the microbe’s and the
host’s. Several examples are illustrated, with the likely outcomes resulting from the varying
“settings” on the host and microbe sides. On the microbe side (the blue column), three factors are
(1) its native virulence (for example, does it produce exotoxins?), (2) how many organisms
encountered the host (how close it is to its optimal infectious dose), and (3) whether it made
contact with the correct portal of entry. On the host side, important factors are (1) natural genetic
variability, which will impact how well components of our defense respond; (2) whether the host
has seen the microbe before, either through infection or vaccination; and (3) the host’s general
level of health. Read each row from left to right to see how one particular interaction turns out.
Let’s look at row 2 as an example from figure 11.5. In this scenario, the anonymous
microbe has a moderate ability to be virulent, it has encountered the host with about half of its
optimal infectious dose, but it did access the correct portal of entry. The host does have a genetic
profile that provides high defenses for this microbe and has seen the microbe before, meaning
that it will have some degree of adaptive immunity. Lastly, the host is generally healthy. So,
even though the microbe has some things going for it, it will not be likely to cause disease but
will simply be transient, or, if it does become established in the host, it will not cause disease.
Spend some time on the other rows and you will gain an appreciation of when an infectious
disease occurs or not.
The earliest symptoms of disease usually come from the activation of the body defense
process called inflammation. The inflammatory response includes cells and chemicals that
respond innately to disruptions in the tissue. Some common symptoms of inflammation include
fever, pain, soreness, and swelling. Signs of inflammation include edema, the accumulation of
fluid in an afflicted tissue; granulomas and abscesses, walled-off collections of inflammatory
cells and microbes in the tissues; and lymphadenitis, swollen lymph nodes.
Changes in the number of circulating white blood cells, as determined by special counts,
are considered to be signs of possible infection. Leukocytosis (loo″-koh′-sy-toh′- sis) is an
increase in the level of white blood cells, whereas leukopenia (loo″-koh-pee′-nee-uh) is a
decrease. Other signs of infection revolve around the occurrence of a microbe or its products in
the blood. The clinical term for blood infection, septicemia, refers to a general state in which
microorganisms are multiplying in the blood and are present in large numbers. When small
numbers of bacteria or viruses are found in the blood, the correct terminology is bacteremia, or
viremia, respectively which means that these microbes are present in the blood but are not
necessarily multiplying. During infection, a normal host will invariably show signs of an
immune response in the form of antibodies in the serum. This fact is the basis for several
serological tests used in diagnosing infectious diseases such as AIDS or syphilis. Such adaptive
immune reactions indicate the body’s attempt to develop specific immunities against pathogens.
Earlier, we introduced the idea that a pathogen is considered unsuccessful if it does not
have a mechanism for leaving its host and moving to other susceptible hosts. With few
exceptions, pathogens depart by a specific avenue called the portal of exit (figure 11.6). In most
cases, the pathogen is shed or released from the body through secretion, excretion, discharge, or
sloughed tissue. The usually very high number of infectious agents in these materials increases
the likelihood that the pathogen will reach other hosts. In many cases, the portal of exit is the
same as the portal of entry, but some pathogens use a different route. As we see in the next
section, the portal of exit is a concern for epidemiologists because it greatly influences the
dissemination of infection in a population.
The apparent recovery of the host does not always mean that the microbe has been
completely removed or destroyed by the host defenses. After the initial symptoms in certain
chronic infectious diseases, the infectious agent retreats into a dormant state called latency.
Throughout this latent state, the microbe can periodically become active and produce a recurrent
disease. The viral agents of herpes simplex, herpes zoster, hepatitis B, AIDS, and Epstein-Barr
can persist in the host for long periods. The agents of syphilis, typhoid fever, tuberculosis, and
malaria can also enter into latent stages. The person harboring a persistent infectious agent may
or may not shed it during the latent stage. If it is shed, such persons are chronic carriers who
serve as sources of infection for the rest of the population. Some diseases leave sequelae (the
medical term for consequences) in the form of long-term or permanent damage to tissues or
organs. For example, meningitis can result in deafness, strep throat can lead to rheumatic heart
disease, Lyme disease can cause arthritis, and polio can produce paralysis.
There are four distinct phases of infection and disease: the incubation period, the
prodrome, the acute period, and the convalescent period. The incubation period is the time from
initial contact with the infectious agent (at the portal of entry) to the appearance of the first
symptoms. During the incubation period, the agent is multiplying at the portal of entry but has
not yet caused enough damage to elicit symptoms. Although this period is relatively well defined
and predictable for each microorganism, it does vary according to host resistance, degree of
virulence, and distance between the target organ and the portal of entry (the farther apart, the
longer the incubation period). Overall, an incubation period can range from several hours in
pneumonic plague to several years in leprosy. The majority of infections, however, have
incubation periods ranging between 2 and 30 days.
The earliest notable symptoms of many infections appear as a vague feeling of
discomfort, such as head and muscle aches, fatigue, upset stomach, and general malaise. This
short period (1–2 days) is known as the prodromal stage. Some diseases have very specific
prodromal symptoms. Next, the infectious agent enters an acute phase, during which it multiplies
at high levels, exhibits its greatest virulence, and becomes well established in its target tissue.
This period is often marked by fever and other prominent and more specific signs and symptoms,
which can include cough, rashes, diarrhea, loss of muscle control, swelling, jaundice, discharge
of exudates, or severe pain, depending on the particular infection. The length of this period is
extremely variable. As the patient begins to respond to the infection, the symptoms decline—
sometimes dramatically, other times slowly. During the recovery that follows, called the
convalescence, the patient’s strength and health gradually return, owing to the healing nature of
the immune response. During this period, many patients stop taking their antibiotics, even though
there are still pathogens in their system. Think about it—the microbes still alive at this stage of
treatment are the ones in the population with the most intrinsic resistance to the antibiotic. In
most cases, continuing the antibiotic dosing will take care of them. But stop taking the drug now
and the bacteria that are left to repopulate are the ones with the higher resistance. These are the
four phases all infectious diseases have. There is a fifth phase, which only some infections have:
the continuation phase, in which either the organism lingers for months, years, or indefinitely
after the patient is completely well or the organism is gone but symptoms continue. Typhoid
fever is one disease in which the organism lingers after the patient has fully recovered. An
example of a disease that lingers after the organism is no longer detectable is syphilis (in some
cases). Chronic Lyme disease can also be put in that catego
Important Features of Infectious Disease Transmission
The list of both living and nonliving reservoirs is presented in table 11.4. You can
probably guess that a great number of infections that affect humans have their reservoirs in other
humans. Persons or animals with obvious symptomatic infection are obvious sources of
infection, but a carrier is, by definition, an individual who inconspicuously shelters a pathogen
and spreads it to others without any notice. The duration of the carrier state can be short or long
term, and it is important to remember that the carrier may or may not have experienced disease
due to the microbe. Several situations can produce the carrier state. Table 11.5 describes the
various carrier states and provides examples of each. Animals as Reservoirs and Sources
Animals deserve special consideration as reservoirs of infections.
The majority of animal reservoir agents are arthropods such as fleas, mosquitoes, flies,
and ticks. Larger animals can also spread infection—for example, mammals (rabies), birds
(psittacosis), or lizards (salmonellosis). Many vectors and animal reservoirs spread their own
infections to humans. An infection indigenous to animals but also transmissible to humans is a
zoonosis (zoh″-uh-noh′-sis). Some zoonotic infections (rabies, for instance) can have multihost
involvement, and others can have very complex cycles in the wild (see plague in chapter 18).
Zoonotic spread of disease is promoted by close associations of humans with animals, and
people in animal-oriented or outdoor professions are at greatest risk. At least 150 zoonoses exist
worldwide; the most common ones are listed in table 11.6. Zoonoses make up a full 70% of all
new emerging diseases worldwide. It is worth noting that zoonotic infections are impossible to
completely eradicate without also eradicating the animal reservoirs.
Infectious diseases can be categorized on the basis of how they are acquired. A disease is
communicable when an infected host can transmit the infectious agent to another host and
establish infection in that host. (Although this terminology is standard, one must realize that it is
not the disease that is communicated but the microbe. Also be aware that the word infectious is
sometimes used interchangeably with the word communicable, but this is not precise usage.) The
transmission of the agent can be direct or indirect, and the ease with which the disease is
transmitted varies considerably from one agent to another. If the agent is highly communicable,
especially through direct contact, the disease is contagious. Influenza and measles move readily
from host to host and, for that reason, are called contagious, whereas Hansen’s disease (leprosy)
is only weakly communicable. Because they can be spread through the population,
communicable diseases are our main focus in the following sections. In contrast, a
noncommunicable infectious disease does not arise through transmission of the infectious agent
from host to host. The infection and disease are acquired through some other special
circumstance. Noncommunicable infections sometimes occur when a compromised person is
invaded by his or her own microbiota. Ear infections are good examples of this. Other instances
of this are when an individual has accidental contact with a microbe that exists in a nonliving
reservoir such as soil. Some examples are certain mycoses, acquired through inhalation of fungal
spores, and tetanus, in which Clostridium tetani spores from a soiled object enter a cut or wound.
Persons with these infections do not become a source of disease to others.
There are many different ways that microbes can be transmitted. They are summarized in
table 11.7. First of all, we speak of horizontal versus vertical transmission. The term horizontal
means the disease is spread through a population from one infected individual to another.
Vertical signifies transmission from parent to offspring via the ovum, sperm, placenta, or milk.
Within the category of horizontal transmission, we can further subdivide the mechanisms into
three broad groups: direct contact, indirect routes, and vector transmission. Direct transmission
involves very close contact between people. Indirect transmission occurs when an object or
substance carries the agent from one person to another. A special category of indirect
transmission is parenteral transmission. It refers to a puncture, in which material from the
environment is deposited directly in deeper tissues. This can be intentional, in the case of
contaminated needles, or unintentional, as in the case of puncture injuries. Lastly, vectors are
arthropods that harbor an infectious agent and transmit it to a human.
Infectious diseases that are acquired or develop during a hospital or health care facility
stay are known as healthcare-associated infections (HAIs), also called nosocomial (nohz″-oh-koh
′-mee-al) infections. This concept seems strange at first thought because a hospital is regarded as
a place to get treatment for a disease, not a place to acquire a disease. Yet it is not uncommon for
a surgical patient’s incision to become infected or a burn patient to develop a case of pneumonia
in the clinical setting. The rate of healthcare-associated infections can be as low as 0.1% or as
high as 20% of all admitted patients, depending on the clinical setting, with an average of about
4%. This adds up to about 750,000 cases in acute care hospitals every year, which result in
nearly 75,000 deaths. When you examine the circumstances, you see that a certain number of
HAIs are virtually unavoidable. After all, the hospital both attracts and creates compromised
patients, and it serves as a collection point for pathogens. Some patients become infected when
surgical procedures or lowered defenses permit resident biota to invade their tissues. Other
patients acquire infections directly or indirectly from fomites, medical equipment, other patients,
medical personnel, visitors, air, and water. The health care process itself increases the likelihood
that infectious agents will be transferred from one patient to another. Indwelling devices such as
catheters, prosthetic heart valves, grafts, drainage tubes, and tracheostomy tubes form ready
portals of entry and habitats for infectious agents. Because such a high proportion of the hospital
population receives antimicrobial drugs during their stay, drug-resistant microbes are selected for
at a much greater rate than is the case outside the hospital.
A new organism has begun to worry U.S. health care officials. A multidrug-resistant
yeast called Candida auris has been causing HAIs in several countries around the world, since
2009. It causes highly invasive infections with high mortality rates. Only one U.S. case was cited
in the CDC alert issued in 2016, but due to its appearance over such a wide geographic area, the
agency issued the alert to encourage hospitals to be on the lookout for it. It worries public health
officials because it is resistant to antifungal agents with different modes of action, seems to have
appeared simultaneously on different continents, and is extremely difficult to eradicate from
contaminated surfaces. Scientists still do not know where the fungus resides in nature, which
makes it difficult to design prevention strategies. Hospitals generally employ an infection control
officer who not only implements proper practices and procedures throughout the hospital but is
also charged with tracking potential outbreaks, identifying breaches in asepsis, and training other
health care workers in aseptic technique. Among those most in need of this training are nurses
and other caregivers whose work, by its very nature, exposes them to needlesticks, infectious
secretions, blood, and physical contact with the patient. The same practices that interrupt the
routes of infection in the patient can also protect the health care worker. It is for this reason that
hospitals have adopted universal precautions that recognize that all secretions from all persons in
the clinical setting are potentially infectious and that transmission can occur in either direction.
The general idea of Koch’s postulates is that you must isolate what you think the cause is,
then apply it to a naive population, and then produce the same effect. This general progression is
still considered the gold standard for determining that any given factor is causing—not simply
correlated with—some observed condition. Many of the media reports you read about the latest
“findings” are based on studies reporting correlations, not causation. Consider the claim that
Facebook usage leads to shorter attention spans. Finding a causative relationship between the
two things would require taking large numbers of people who had never used Facebook,
measuring their attention spans, and then forcing them to use Facebook for some allotted time
period. Then you would need to remeasure their attention spans. This would approach the gold
standard of Koch’s postulates, although you would not be able to completely hold all other
variables constant in your subjects, unless you kept them all in your laboratory for the whole
duration of your experiment. So you begin to see how difficult true causation is to prove.
Koch’s postulates are reliable for many infectious diseases, but they cannot be
completely fulfilled in certain situations. For example, some infectious agents are not readily
isolated or grown in the laboratory. If one cannot elicit an infection similar to that seen in
humans by inoculating it into an animal, it is very difficult to prove the etiology. It is difficult to
satisfy Koch’s postulates for viral diseases because viruses usually have a very narrow host
range. Human viruses may cause disease only in humans, or perhaps in primates, though the
disease symptoms in apes will often be different. To address this, there are modified postulates
for viral infections. One very important reason Koch’s postulates are increasingly viewed with
caution is the idea, presented earlier, that perhaps the majority of human infections are
polymicrobial. In those infections, Koch’s postulates cannot be satisfied.
Epidemiology: The Study of Disease in Populations
So far, our discussion has revolved primarily around the impact of an infectious disease
in a single individual. Let us now turn our attention to the effects of diseases on the community
—the realm of epidemiology. By definition, this term involves the study of the frequency and
distribution of disease and other health-related factors in defined populations. It involves many
disciplines—not only microbiology but also anatomy, physiology, immunology, medicine,
psychology, sociology, ecology, and statistics—and it considers all forms of disease, including
heart disease, cancer, drug addiction, and mental illness. A groundbreaking British nurse named
Florence Nightingale helped to lay the foundations of modern epidemiology. She arrived in the
Crimean war zone in Turkey in the mid-1850s, where the British were fighting and dying at an
astonishing rate. Estimates suggest that 20% of the soldiers there died (by contrast, 2.6% of U.S.
soldiers in the Vietnam War died). Even though this was some years before the discovery of the
germ theory, Nightingale understood that filth contributed to disease and instituted methods that
had never been seen in military field hospitals. She insisted that separate linens and towels be
used for each patient, and that the floors be cleaned and the pipes of sewage unclogged. She kept
meticulous notes of what was killing the patients and was able to demonstrate that many more
men died of disease than of their traumatic injuries. She used statistical analysis to convince
government officials that these patterns were real. This was indeed one of the earliest forays into
epidemiology—trying to understand how diseases were being transmitted and using statistics to
do so. Epidemiologists try to identify causative agents, using adaptations of Koch’s postulates
when the disease is not an infectious disease, or using mostly nonexperimental types of analyses.
The techniques of epidemiology are also used to track behaviors, such as exercise or smoking.
The epidemiologist is a medical sleuth who collects clues on the causative agent, pathology,
sources, and modes of transmission and tracks the numbers and distribution of cases of disease in
the community. The outcomes of these studies help public health departments develop
prevention and treatment programs and establish a basis for predictions.
A well-developed network of individuals and agencies at the local, district, state,
national, and international levels keeps track of infectious diseases. Physicians and hospitals
report all notifiable diseases that are brought to their attention. These reports are made either
about individuals or in the aggregate, depending on the disease. The Internet has revolutionized
disease tracking. For example, a few years ago Google launched a service that used trending
search terms (“fever,” “flu symptoms”) to predict flu outbreaks, theoretically faster than
traditional surveillance methods. It had some flaws, but other companies have improved on the
concept. Most experts expect that this use of what is known as “big data” promises to speed up
prediction and response time for disease outbreaks.
Changes in incidence and prevalence are usually followed over a seasonal, yearly, and
long-term basis and are helpful in predicting trends (figure 11.9). Also of concern to the
epidemiologist are the rates of disease with regard to sex, race, or geographic region. Figure
11.9a displays incidence trends over time as well as within different age groups; figure 11.9b
shows another way of depicting epidemiological data, in a map format. Also of importance is the
mortality rate, which measures the total number of deaths in a population due to a certain
disease. Over the past century, the overall death rate from infectious diseases in the developed
world has dropped, although the number of persons afflicted with infectious diseases (the
morbidity rate) has remained relatively high. Clearly, different infections have differing degrees
of communicability in populations. They also have varying abilities to cause death. When
epidemiologists keep track of mortality rates, they can use these as predictive tools. As they keep
track of incidence rates in epidemic and nonepidemic situations, they can calculate a factor
called the reproductive rate (R 0) of a disease. That is also extremely useful in predicting and
managing the spread of infectious disease. Please take a look at the Note near the end of the
chapter About Epidemiology: Communicability and Deadliness in which we introduce these two
important characteristics of infectious disease. In each of the disease chapters, we will circle
back to the two triangles introduced here.
When there is an increase in disease in a particular geographic area, it can be helpful to
examine the epidemic curve—which is incidence plotted over time—to determine if the infection
is a commonsource or propagated epidemic. A common-source epidemic, illustrated in figure
11.10a, is one in which the infectious agent was present in a single source that had widespread
distribution, infecting people in a wide geographic area. When food is contaminated at a factory,
it can result in commonsource epidemics. A particular type of common-source epidemic is
referred to as point-source epidemic. It is still a common source, but usually it is a single small
batch of food or water that was contaminated, and everyone was infected at once, such as spoiled
potato salad at a church picnic. That curve would have a much shorter time span on the
horizontal axis. A propagated epidemic (figure 11.10b) results from an infectious agent that is
communicable from person to person and therefore is sustained—propagated—over time in a
population. Influenza is the classic example of this. The graph illustrates an entire year of
influenza incidence in the United States. In propagated epidemics, the incidence constantly
increases until it peaks, then begins to decrease due to natural factors or due to control measures.
Each year the influenza epidemic curve has a similar shape. The end of the epidemic is due to
features of the virus, not to control measures.
