Download MRSA_6-6-10_jas

1
Chapter 6
Challenge of Antimicrobial Resistance: MRSA and More
Introduction
Since the first sulfa drugs became available in the 1930’s, antimicrobial drugs
have been hailed as miracle drugs that have saved millions of lives. However, with
each passing decade more bacteria have become resistant to either single antibiotics
or multiple antibiotics making some diseases more difficult to control. Most
clinically important bacteria, viruses and protozoan have now developed strains that
are resistant to some antimicrobials. Increased antimicrobial resistance can lead to
more visits to the doctor, more hospitalizations, lengthier illnesses and more deaths.
Addressing the challenge of antimicrobial resistance requires a partnership between
prescribers, patients, hospitals, pharmaceutical companies, government agencies, and
livestock feeding operations.
In this chapter we will explore the development of antibiotic resistance
strains of Staphylococcus aureus, called MRSA, and investigate the extent of the
problem. We will then explore other examples of antibiotic resistance and examine
how surveillance of antibiotic resistant bacteria can be used to develop criteria for
prudent use of antibiotics. We will then investigate how physicians, consumers and
policy makers might reduce the incidence of antibiotic resistant infections.
Investigation 1: MRSA on campus
The coach of the football team from your college has suddenly
become obsessively clean, insisting that everyone showers after practice, that
no one shares towels, and
that all scraped shins are
cleaned and bandaged as
soon as possible. (Figure
6-1) When asked by the
student newspaper why
he suddenly changed his
behavior, he replied that
one of the teams in the
conference had several
students who had
developed skin infections
that tested positive for
Figure 6-1. MRSA education poster
MRSA, and one athlete
was hospitalized with
necrotizing fasciitis. He didn’t want any of that for his team.
1. In a small group, discuss and complete Table 6-1 listing “What”
you already know about MRSA, and “What” you need to know.
2
Table 6-1. What do I Know? What do I need to know?
What Do I Know?
What Do I Need to Know?
2. The coach in the introductory story was concerned about MRSA
spreading through his team. Develop a one-page brochure to
explain to athletes why their attention to good hygiene is
important in the locker room and the weight room.
The brochure should briefly describe what MRSA infections are
and what they look like. Prevention details should address
personal hygiene, sharing personal items such as towels, and care
of scratches and wounds.
Resources for investigation:
Video about MRSA in high schools
http://www.youtube.com/watch?v=GrySW5FeCmU
MRSA among athletes
http://www.cdc.gov/ncidod/dhqp/ar_MRSA_AthletesFAQ.html
Case on USC football team
http://www.aaos.org/news/bulletin/oct07/clinical1.asp
Living with MRSA
http://www.tpchd.org/files/library/463bf2a956f3d453.pdf
3
Biology of MRSA
Methicillin-resistant Staphylococcus aureus, MRSA (pronounced mersa), are
a group of staphylococcal strains that are resistant to methicillin and other related
antibiotics such as penicillin, oxacillin and
cephalosporins. These resistance traits make these
normally treatable bacteria hard to kill and make
infections potentially deadly. S. aureus is a sphereshaped, gram-positive bacterium which is part of the
normal microbiota of the skin and nasal passages.
(Figure 6-2) Most “staph” infections are not caused by
MRSA and non-MRSA strains are usually easier to
treat than infections caused by MRSA.
One study estimates that there were 94,360
hospitalizations for invasive MRSA infections in the
Figure 6-2. S. aureus bacteria
escaping destruction by human
US in 2005, and 18,650 hospital deaths due to these
white blood cells. (Credit:
infections. (Klevens, 2007) About 85% of these
NIAID/RML)
infections were associated with healthcare and 14%
were associated with the community. In the U.S., hospital-acquired MRSA (HAMRSA) infections have been a problem since the 1960’s and made up 64.4% of the
infections caused by S. aureus in intensive care units (Klevens, 2006). Communityacquired MRSA (CA-MRSA) infections started emerging in the late 1990’s. The
failure of antibiotics to treat common bacterial infections like S. aureus has led
physicians to worry about the potential end of the era of antibiotics and the need to
resort to older and more toxic drugs. (Arias and Murray, 2009)
When penicillin was first produced, strains of S. aureus were sensitive to the
antibiotic. However, a plasmid-borne gene for penicillin resistance has made some
strains of Staphylococcus resistant to penicillin. (Read on to learn more about
plasmids and antibiotic resistance genes.) Semi-synthetic versions of penicillin such
as methicillin were introduced to circumvent resistance but bacteria developed
resistance for those antibiotics as well. Methicillin is no longer used in the United
States and the term “MRSA” has come to mean strains of S. aureus that are resistant
to many antibiotics related to penicillin and methicillin.
In 2004 approximately 29% of the U.S. population silently carried nonMRSA S. aureus while 1.5% silently carried MRSA. (Gorwitz, 2007) Physicians and
microbiologists say that these people were “colonized” by the bacteria. Infections
occur when these bacteria bypass the barriers of the immune system and enter the
body through cuts and scrapes where they are able to multiply and produce toxins.
Investigation 2: How do HA-MRSA strains differ from CA-MRSA strains?
The location and severity of infections caused by CA-MRSA and HAMRSA differ. In general the community associated infections are less severe
and respond better to treatment because they are susceptible to a number of
antibiotics which can be used to treat the infection. CA-MRSA infections
often occur in different tissues than HA-MRSA strains. Figure 6-3 shows the
4
predominant sites infected by CA-MRSA. HA-MRSA strains are resistant to
many antibiotics and colonize more invasive sites making them more difficult
to treat. The spectrum of disease caused by HA-MRSA infections in
hospitalized patients is shown in Fig. 6.4.
Figure 6-3. Locations and percentages of CA-MRSA infections
Figure 6-4. Locations and percentages of HA-MRSA infections
5
1. Contrast the infection site locations for HA-MSRA and CAMRSA. List two observations and suggest an explanation for
each trend. Use Internet sources to help explain the trends.
The location frequencies for infection sites for CA-MRSA and
HA-MRSA are totally different. The most frequent site for CAMRSA is skin/soft tissue while for HA-MRSA it is bacteremia.
Skin/soft tissue infections occurred 76% of the time with CAMRSA infections and only 9.7% (cellulitis) with HA-MRSA.
Bacteremia occurred 2.6% of the time with CA-MRSA infections
and 75.2% with HA-MRSA. Patients in hospitals undergo various
procedures such as venapuncture and surgery expose them to
possible infections of other tissues besides skin. They also have
underlying health conditions that may lower their resistance.
2. The CDC provides educational materials about MRSA for
healthcare professionals. Explore this CDC site and linked pages
to learn more about MRSA, taking a look at the photos of
infections, reading about HA-MRSA and CA-MRAS, and
checking out the links on “Prevention.” Read the algorithm for
treatment of CA-MRSA and eradication of MRSA colonization in
individuals who have become carriers. Complete Table 6-2.
Resources for investigation:
CDC MRSA site
http://www.cdc.gov/mrsa/mrsa_initiative/skin_infection/
Algorithm for treating MRSA
http://www.tpchd.org/files/library/37cdc74cac9cb379.pdf
Table 6-2. Characteristics of CA-MRSA and HA-MRSA strains
Characteristic
Type of infections
At-risk populations
CA-MRSA
skin infections:
abscesses, boils, and
other pus-filled lesions
& groups such as
athletes, military,
prisoners
Patient’s under-lying
conditions
None
Age group
Younger
HA-MRSA
Pneumonia,
septicemia, urinary
tract, wounds
Associated with
outbreaks in health
care facilities
Health-care related
procedures:
incisions, catheters,
dialysis
Older
6
Antimicrobial resistance
Susceptible to multiple
antibiotics
PVL: cytotoxin produced by
bacteria that kills white blood
Many strains
cells, monocytes and
macrophages; increases
virulence of bacteria
Prevalent genotypes (U.S.)
USA300, USA400
Resistant to multiple
antibiotics
Few strains
USA100, USA200
Investigation 3: Transmission and epidemiology of MRSA
The first steps to designing a program to lower the incidence of the
disease are to understand how the pathogen causes disease, learn how it is
transmitted, and conduct epidemiological studies. Epidemiology is the study
of the distribution and incidence of a disease using surveillance data and
other data sets as appropriate. In this investigation we will use data sets to
better understand transmission patterns. We will begin with an example of a
hospital infection-control team gathering data to track down the source of an
outbreak of MRSA.
Between May-December a large hospital in Chicago reported a cluster
of MRSA skin infections in babies born in the nursery and in most cases sent
home. The average age of the babies was 7 days. (MMWR, 2006) Ten
infants received topical antibiotics and three of those infants also received
oral antibiotics. The 11th infant was hospitalized for the infection and
received antibiotics; all the infants recovered. There was no indication that
family members of the infants had skin infections that were caused by
MRSA. Nasal cultures were taken from 135 healthcare workers (HCW) from
the labor and delivery, postnatal, and newborn nursery wards. Two HCW, a
physician and a nurse, were found to be colonized with the same strain of
MRSA that was isolated from 6 infants who were cultured. The strain was a
USA300, typical of CA-MRSA, and had previously been isolated from
nursery outbreaks in Los Angeles and New York. In-service training was
held for the wards listed above and the two colonized individuals were
treated with intranasal mupirocin, an antibiotic, to clear the MRSA from their
nostrils.
1. One of the challenges in tracking down the source of the infection
is that there are time, money and practical limitations on the
amount of testing that can be completed. With these limitations,
the investigator tries to put the pieces of the puzzle together.
a. How do you think this outbreak started? Generate two
possible explanations.
7
MRSA could have been introduced to the nursery by a family
member who was colonized with MRSA but did not have an
active infection. The MRSA could have been transferred from
one baby to another during routine baby care. The healthcare
workers could have been colonized from the infected babies.
Colonized, non-symptomatic healthcare workers could have
introduced MRSA to the nursery and it could have spread among
the babies during routine care.
b. In an ideal world what data would you collect to confirm
the source of the infection? Explain.
Ideally it would have been good to culture all the family members
that were in contact with the babies to see if they were colonized.
Also, taking histories of the culture-positive healthcare workers
and family members might have helped with developing a
timeline.
The Biology of Antibiotic Resistance
The development of antibiotics in the
1930s and 1940s dramatically changed healthcare
around the world. Bacterial infections that had
been deadly were suddenly curable. Childhood
ear infections didn’t progress to cause deafness.
Sexually transmitted infections like gonorrhea and
syphilis were curable. Sulfa drugs, introduced in
1932, were widely used by the Allied Forces in
Figure 6-5. U.S.
WWII. By 1941 penicillin was being produced in
Department of Health &
large-scale batches and was used during the war to
Services
treat infections. (Figure 6-5)
Antibiotics are naturally occurring or
synthetically produced chemicals that can kill bacteria by interrupting their
metabolism and reproduction. Antibiotics work by targeting metabolic functions that
differ between bacterial cells and eukaryotic (nucleus containing; make up human
tissue) cells, allowing them to harm bacteria without harming the host.
As the medical world was marveling at the success of these drugs, few
predicted the evolution of antibiotic resistant strains and the struggle to develop new
drugs to avoid the resistance. However, by 1944 the first penicillin resistant strains
appeared in hospitals and after six years they made up 25% of the Staphylococcus
aureus hospital isolates. (Figure 6-6) These resistant strains produced an enzyme,
called penicillinase, which inactivated penicillin.
Figure 6-6. Increase in the prevalence of penicillinase-producing, methicillinsusceptible strains of Staphylococcus aureus in hospitals (closed symbols) and the
community (open symbols). (Chambers, 2001)
8
Antibiotic resistance is the ability of bacterial strains to grow in the presence
of an antibiotic. In a large population of bacteria, a few cells may become resistant
to the antibiotic and through natural selection those bacterial types survive and
reproduce to become the predominant organisms in the population. (Figure 6-7)
Figure 6-7. Development of antibiotic resistance in bacteria. (Jones & Bartlett,
Pommerville, Alcamo's Fundamentals of Microbiology, 8th Edition, Figure 24.14)
Antibiotic resistance may develop in a bacterial cell due to a mutation in its
DNA that changes one of the targets of the antibiotic or gives the cell the ability to
destroy, inactivate or pump out the antibiotic. Since the changes are in the DNA, the
new traits can then be passed on to other cells. Sometimes the antibiotic resistant
genes in bacteria are carried on small, circular pieces of DNA called plasmids.
Plasmids are independent of the bacterial chromosome and can replicate. Antibiotic
resistance genes carried on plasmids can spread resistance to bacteria of the same or
different species. Figure 6-8 shows other ways that bacteria transfer genetic material
to other cells.
9
Figure 6-8. Bacterial gene transfer can be vertical or horizontal
Investigation 4: Antibiotic resistance affects treatment options
Look at the tutorial, Antibiotics attack, on the Howard Hughes
Medical Institute site and focus on the “Antibiotic resistance” section to learn
more about how resistance is spread between organisms. Explore the related
material in the online textbook site. Next watch “Super Bugs-Bacterial
Resistance” on YouTube.
1. In the video, “Super Bugs-Bacterial Resistance,” Steptococcus
pneumoniae (pneumococcus) was used as an example of a
bacterial species with strains that had developed resistance to
several antibiotics. The CDC reports that 38% of the isolates for
this organism, which causes a type of pneumonia, a type of
meningitis and some ear infections, are resistant to at least one
antibiotic. In late 2000 a vaccine for pneumococcus was approved
by the FDA for use in children and is included in the standard US
immunization schedule. Since the introduction of this vaccine, the
incidence of antibiotic-resistant strains of S. pneumoniae has
declined. How would you explain this decrease in antibioticresistant strains?
10
There was a decrease in the number of cases of disease caused by
Streptococcus pneumoniae after the vaccine was introduced. With
fewer cases, fewer antibiotics were prescribed for the organism
and resistant strains were less likely to develop.
2. Patients being treated for tuberculosis may be prescribed as many
as four antibiotics at the same time, e.g. rifampin, ethambutol,
isoniazid, and pyrazinamide. In addition, patients are observed
taking their medications under a program called “directly
observed treatment” (DOT) to insure that the treatment plan is
followed. Why is this strategy used?
If patients are treated with multiple drugs there is less likelihood
of resistant strains developing. If the organism develops
resistance to one antibiotic, the other antibiotics will still be active
and kill the strain. Using antibiotics with different modes of
action helps prevent resistant strains from developing, too. It is
important to maintain even drug levels in the body.
Resources for investigation:
Howard Hughes Medical Institute
http://www.hhmi.org/biointeractive/Antibiotics_Attack/frameset.html
Online textbook
http://textbookofbacteriology.net/resantimicrobial.html
Super Bugs-Bacterial Resistance
http://www.youtube.com/watch?v=VQhIz2LqrYA&feature=channel_
page
Treatment of Tuberulosis
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5211a1.htm#tab3
3. Antibiotic resistance has evolved in many different types of
pathogens besides Staphylococcus aureus. Choose a disease agent
from the list in Table 6.5 and prepare a description of the
organism, the symptoms of the condition that it causes and the
consequences of antibiotic resistance. If possible, identify the
resistance strategies used by the pathogen. Use the resources of
the Centers for Disease Control, World Health Organization and
other web sources.
Students should write one to two pages on the organism that they
choose describing the diseases it causes, the antibiotic treatments
11
that are used, the development of antibiotic resistant strains and
the challenges faced in treating the disease.
Resources for investigation:
Diseases connected to antibiotic resistance
http://www.cdc.gov/drugresistance/diseases.htm
Publications on antibiotic resistance
http://www.cdc.gov/drugresistance/publications.htm
Table 6.5. Examples of pathogens that have developed antibiotic resistant
strains.
Organism
Enterococcus
Streptococcus pneumoniae
Streptococcus pyogenese
Pseudomonas aeruginosa
Clostridium difficile
Escherichia coli
Staphylococcus aureus
Mycobacterium tuberculosis
Plasmodium sp. (protozoan)
Trypanosoma brucei
rhodesiense and Trypanosomoa
brucei gambiense
Clinical Infection
Urinary tract infections, bacteremia,
bacterial endocarditis, diverticulitis, and
meningitis
Pneumonia, bacteremia, otitis media,
meningitis, sinusitis,
Skin infections, cellulitis, impetigo
Opportunistic infections, skin infections
Diarrheal disease
Bladder infections, GI tract infections
Skin infections, pneumonia, sepsis
TB
Malaria
Sleeping sickness
4. Resistance vs. Virulence: The news media often refer to antibiotic
resistance occurring in a strain of bacteria and then proceed to
refer to the organism as being virulent. Resistance and virulence
are two different characteristics of bacteria. Virulence factors are
responsible for aiding bacteria to invade the host tissue and
establish themselves as pathogens. They are either enzymes
secreted by the bacteria or toxins produced by the bacteria.
Staphylococcus sp. produces a number of virulence factors which
vary from strain to strain. One factor, Panton-Valentine
Leukocidin (PVL), is produced by many CA-MRSA strains but
not the HA-MRSA strains. PVL is a cytotoxin that kills white
12
blood cells, monocytes and macrophages by forming holes in the
cell membranes. How does the activity of PVL make the bacteria
more invasive? Does PVL affect the antibiotic resistance of
Staphylococcus?
PVL is a toxin that causes holes to form in the cell membrane of
white blood cells, monocytes and macrophages at the site of the
infection. Damaging the immune defense cells gives the bacteria
more time to establish themselves as pathogens. It does not affect
the antimicrobial resistance of the organism.
Resources for investigation:
PVL activity
http://en.wikipedia.org/wiki/Panton-Valentine_leukocidin
Invasive factors
http://textbookofbacteriology.net/colonization_3.html
Biofilm Formation Increases Resistance to Antibiotics
Bacteria are most often thought of as single cells, or small chains or clusters
of cells that act independently and do not need to be attached to a surface to express
their genes. Over the last 20 years scientists have learned that bacteria in many
environments are not free-floating and independent, referred to as planktonic
bacteria, but are actually organized into layers growing on surfaces. These organized
communities, called biofilms, are found in the soil, fresh and salt water, foods,
manufacturing plants, the cow’s rumen, the human body and many other places.
The biofilms begins to form when planktonic bacteria attach to a surface and
establish themselves. The attachment triggers physiological changes that stimulate
the cells to grow, divide and secrete a complex mixture of polysaccharides, DNA and
proteins that make up the “slime” layer that we call biofilms. Cells are able to
release signaling molecules to chemically communicate with each other and detect
conditions such as cell density or the presence of antibiotics. This signaling, called
quorum sensing, enables the group of individual cells to coordinate their response to
the environment. The process of biofilm formation is shown Fig. 6-9.
13
Fig 6-9. Formation of a biofilm. (Harrison et al., 2005)
Biofilms are involved in many diseases such as endocarditis, lung infections
in cystic fibrosis, ear infections, and dental plaque. Medical implants such as
artificial heart valves, joint replacements and indwelling catheters can support the
growth of biofilms which become the source of infection. Biofilms can contain one
to several species of bacteria which can communicate and transfer genes between
each other.
Although they don’t look like it under a light microscope, biofilms are
actually well organized with channels for water, nutrients and oxygen and persister
cells that are metabolically modified to increase their survival under adverse
conditions. An example of how a biofilms might be organized is shown in Fig. 6-10.
14
Fig. 6-10. Example of biofilm structure. (Harrison et al., 2005)
Bacteria in biofilms resist antibiotics in several ways that are not available to
individual cells, including 1) quorum sensing systems of communication, 2)
decreased penetration of the antibiotic into the biofilms matrix, 3) increased use of
cellular pumps to keep antibiotics out of the cells and 4) genetic switches that turn
susceptible cells into antibiotic-resistance persister cells. (Leid, 2009) Antibiotic
treatments may kill susceptible cells but persister cells can remain in the biofilms
matrix and grow after the antibiotic concentration goes down.
Biofilms also protect bacteria by affecting the response of the immune system
against the bacterial cells. Leukocytes and their products as well as phagocytes are
limited in their ability to invade the biofilms and act on the bacteria. (Leid, 2009)
Investigation 5: Persistent Middle Ear Infections
1. Some children respond to antibiotic treatment of a middle ear
infection and do not have frequent recurrences while other
children have recurring infections every few weeks. Describe the
sequence of events that could lead to recurring ear infections.
Resources for investigation:
Biofilm Basics: An introduction
http://www.biofilm.montana.edu/biofilm-basics.html
15
Slideshow of household biofilms
http://www.biofilm.montana.edu/content/household-biofilms
Ear infections and biofilms
http://www.technologyreview.com/Biotech/17150/
YouTube video on biofilms
http://www.youtube.com/watch?v=XVJ6FQTIDG8
Finding the Source of Antibiotic Resistant Bacteria
What is the source of antibiotic resistant bacteria and why are they becoming
more common? Antibiotic resistance initially develops in a cell due to a mutation in
the DNA. The new resistant gene can be spread to other organisms by horizontal
transfer using the mechanisms of transformation and more often conjugation. Many
resistant genes originally came from environmental organisms found in soil, water
and food (Marshall et al., 2009). Soil organisms produce a variety of antibiotics
which serve as both “weapons” to protect themselves from competition with other
species and as chemical signals between cells. Antibiotic resistant genes likely
evolved at the same time as the antibiotic genes and helped the cells resist the
“weapons” action of antibiotics from other organisms. Thus, the environmental
organisms became a reservoir for antibiotic resistance genes.
Humans and other animals are regularly exposed to bacteria from
environmental sources and some of these bacteria can become transient colonizers of
our skin, nose, throat and intestinal tract. These organisms develop a commensal
relationship with humans and animals, defined as a relationship in which one
organism (the bacteria) benefits and the other organism (human) is not harmed. They
are referred to as transient because they only temporarily reside on the human.
During their temporary residence on the human, there is the opportunity for
horizontal gene transfer of antibiotic resistance genes from the transient commensals
to the core colonizers or normal flora of the human (Marshall et al., 2009). The next
step in the transfer of antibiotic genes occurs when pathogens and opportunistic
pathogens receive the antibiotic resistance genes through conjugation or
transformation.
Overuse of Prescription Antibiotics Increases Antibiotic Resistance
The overuse use and the inappropriate use of antibiotics in medicine are
thought be the major cause for an increase in antibiotic resistant, pathogenic bacteria.
The more antibiotics that are prescribed, the more selective pressure there is for
resistant strains to survive and cause future infections.
A recent study in Europe looked at the rate of antibiotic consumption versus
the incidence of antimicrobial resistance for 21 countries. The data came from the
European Surveillance of Antimicrobial Consumption (ESAC) and the European
Antimicrobial Resistance Surveillance System (EARSS). These two organizations
compile surveillance data from Europe and make it available on interactive web
sites. Figures 6-11 and 6-12 below were based this data base.
16
Investigation 6: Relationship between antibiotic use and incidence of
antibiotic resistance
1. Use Figures 6-11 and 6-12 to answer the questions below. The
data are based on defined daily dose (DDD) which is defined by
the WHO as the average maintenance dose per day per adult.
a. Examine the graphs to determine if there is a correlation
between the amount of antibiotic consumption and the percent
of antibiotic resistant infections. Write one to two paragraphs
answering these questions: Were the countries that used the
lowest amount of antibiotics the same as the countries that had
the lowest percent resistance? Were the countries that used
the highest amount of antibiotics the same as the countries
with the highest percent resistance? What were the
differences?
b. What types of country-specific differences could affect the
data? (e.g. vaccination policy)
Four of the 7 countries that prescribed the lowest amount of
antibiotics were also in the lowest group of 7 countries for
antibiotic resistance: Denmark, Netherlands, United
Kingdom, and Sweden. Four of the six countries using the
most antibiotics were also in the top six countries for
antibiotic resistance: Luxemburg, Portugal, Belgium and
France. One difference is that antibiotics were highly
prescribed in Greece but Greece has a low resistance rate.
There is a note that the data for Greece is incomplete.
Items that could affect the country wide data include:
vaccination policy, regional differences in prescription rates
within a country, general availability and access to health care,
hygiene, infection control measures and consumer attitudes.
17
Figure 6-11. Total antimicrobial drug consumption in outpatient care in DDD per
1000 inhabitants per day (DID) by antimicrobial class in 21 European countries in
2006. (van de Sande-Bruinsma, 2008)
Country designations: AT, Austria; BE, Belgium; BG, Bulgaria; CZ, Czech
Republic; DE, Germany; DK, Denmark; ES, Spain; FI, Finland; FR, France; GR,
Greece; HR, Croatia; HU, Hungary; IE, Ireland; LU, Luxembourg; NL, the
Netherlands; PT, Portugal; SE, Sweden; SI, Slovenia; SK, Slovakia; UK, United
Kingdom.
Figure 6-12. Proportion of penicillin-nonsusceptible Streptococcus pneumonia
(PNSP), erythromycin-nonsusceptible S. pneumonia (ENSP), and fluoroquinoloneresistant Escherichia coli (FQRE) in 2005, ranked in descending order by countries
with the highest percent resistance to lowest as indicated by number above the bars.
(van de Sande-Bruinsma, 2008) (* = Incomplete data)
18
2. The first European Antibiotics Awareness Day was held in 2008.
View the video and look at the fact sheet that was designed for the
Day. The Centers for Disease Control in the US has also designed
an antibiotic awareness program called “Get Smart about
Antibiotics.” The first event was held in fall 2008, and was
repeated in October 2009. Review the materials at the CDC
website.
a. Health promotion and health education are important
aspects of public health programs. If you were designing
an antibiotic awareness day for a large, populous and
diverse country like the U.S., what factors would you need
to keep in mind?
b. Write an article for your college newspaper or your
community newspaper to raise awareness about the
conditions that lead to antibiotic resistance. Remember to
adapt your message to the audience you are targeting. Use
your own words.
Some factors to consider include: language of materials, ways
to communicate with different generations, variety of health
19
care delivery options, reaching people who do not use media,
targeting primary care physicians, and delivery to school-age
children.
Resources for investigation:
European Antibiotics Awareness Day
http://ecdc.europa.eu/en/EAAD/Pages/Home.aspx/
CDC Get Smart about Antibiotics
http://www.cdc.gov/getsmart/campaign-materials/week.html
Self medication with antibiotics can contribute to an increase in antibiotic
resistance in the community. A recent survey in 19 countries of Europe showed that
from 1 to 200 people per 1000 inhabitants took antibiotics without seeking a doctor’s
opinion. From 80 to 449 people per 1000 inhabitants intended to self medicate if
needed. (Grigoryan, 2006) In some cases people were able to obtain the antibiotics
from pharmacies without prescriptions, even though this was against the law in the
countries covered in this survey. Others had left-over antibiotics at home.
Antibiotics are available from pharmacies without a prescription in many
parts of the world even though the country may have laws controlling the how the
drugs are dispensed. On every continent there are towns where people can go to the
pharmacy and buy antibiotics for their infections on the advice of the pharmacist.
Unfortunately, some of the infections are caused by viruses which don’t respond to
bacterial antibiotics and some infections are caused by bacteria resistant to the
antibiotic.
3. Read the article, “Are we killing the cures?” from the Pan
American Health.
a. Describe at least two things that can occur when a person
buys antibiotics from the pharmacy without a prescription.
b. Explain how these actions promote the development of
antibiotic resistance?
When people buy antibiotics from a pharmacy without a
prescription, they may only buy enough for one or a few days.
They may buy the wrong antibiotic for the infection or one that is
no longer effective due to the development of antibiotic
resistance.
Buying an insufficient amount of antibiotic leads to the drug
killing the most susceptible organisms while leaving the more
resistant cells to grow. This applies both to the species that is
causing the infection and other bacteria in the body. Using the
wrong drug unnecessarily exposes the microbial flora of the body
to antibiotics and resistant survive while sensitive strains die.
20
Self-medication may lead to a more serious infection if the drug is
not effective. The patient may end up with a longer illness and
higher exposure to antibiotics.
Resources for investigation:
Are we killing the cures?
http://www.tufts.edu/med/apua/Pubs/Articles/PerspectivesInHealthM
aga.pdf
Agriculture and Antibiotic Resistance
Antibiotics are added to animal feed for the therapeutic treatment of disease,
the prevention of disease, and at low levels for growth promotion. Low levels of
certain antibiotics are used for long periods of time to increase the growth rate of
livestock while therapeutic treatment uses high levels for short periods of time to
treat a specific infection.
The Union of Concerned Scientists estimates that at least 24.6 million pounds
of antibiotics are used each year in animal (poultry, swine, and cattle) agriculture.
This compares with 3 million pounds of antibiotics used in human medicine, or oneeighth the amount used in farm animals. Of the 24.6 million pounds, about 70% are
used for non-therapeutic purposes such as growth promotion.
The presence of antibiotics in animal feed creates selective pressure by
inhibiting the antibiotic-sensitive bacteria and allowing the resistant organisms to
grow. Organisms of particular concern are animal pathogens that can cause disease
in humans and organisms that can colonize humans as commensal bacteria. When
commensals develop antibiotic resistance and colonize humans, they can transfer
their resistance genes to human pathogens. Salmonella sp. and Campylobacter are
two examples of animal pathogens that can cause zoonoses, animal diseases that
occur in humans.
Investigation 7: From Farm to Food to Family
1. The flow chart in Figure 6-13 shows possible ways that antibioticresistant bacteria can be transferred from the farm to humans and
indicates some of the outcomes.
a. Describe how antibiotic-resistant bacteria might be spread
to the community by humans in direct contact with the
animals. Explain the pathway from the farm to the food
production plant to humans.
b. Are more humans likely to pick up bacteria directly from
the live animals or from the food chain? Explain. Why is
there an arrow from humans to hospital-acquired
infections?
21
The flow of antibiotic resistance bacteria (ARB) from the
farm to the community by direct human contact involves
farm workers acquiring ARB from handling the animals.
From the workers ARB can be transferred to family; and
from family to others in the community through school,
sports and other contact. The ARB may not be human
pathogens but the resistance genes can be transferred from
the commensal organisms to pathogens in the human body.
The path through food production begins with ARB
getting on meat during slaughter and being carried to meat
markets and purchased by consumers who pick up the
ARB in the kitchen or in undercooked foods. Fruits and
vegetables can pick up ARB from contaminated soil and
water. These foods may go to the market fresh and carry
organisms into people’s kitchens or may be partially
processed, e.g. shredded lettuce, and then purchased.
There are more opportunities for ARB to move into the
community through the food production route.
People who are colonized with antibiotic-resistant
organisms may enter the hospital for reasons other than
infection. During the hospitalization the antibioticresistant organisms may cause an infection secondary to
the patient’s main diagnosis. This infection can be spread
to other patients and staff if infection control measures
fail.
22
Figure 6-13. Flow chart for the potential movement of antibiotic resistant bacteria
from the agricultural setting to community and healthcare settings. (Adapted from
Sørum, Smith, and Martínez)
Key: HA = hospital-acquired, CA = community-acquired, Carrier = human
colonized with resistant-bacteria but not ill, Infection cleared = human recovered
from infection and did not become a carrier
The non-therapeutic use of antibiotics as growth promoters has been
actively debated for years around the world. There is substanial evidence that
non-therapeutic use of antibiotics does exert selective pressure for resistant
bacteria. For example, in Denmark chicken and pig producers volutarily
stopped using antibiotic growth promoters and saw a significant reduction in
the percent of antibiotic resistant bacteria in their animals. (Aarestrup, 2001)
Food producers had warned that more pathogens could enter the food chain if
non-therapeutic antibiotics were banned.
The European Union banned the use of antibiotics as growth
promoters in animal feeds in January 2006 based on the “precautionary
principle.” The precautionary principle states that if the body of evidence
supports that a process is harmful, even if there is not complete scientific
concensus, then action should be taken to protect the public. As more
evidence becomes available in the future, the action can be modified.
In the U.S., legislation has been introduced several times to preserve
antibiotics for human medical treatment by cutting back on non-therapeutic
use in animal feeds. The legislation is supported by consumer, environmental
and medical groups but opposed by agricultural groups. Agricultural groups
make the point that researchers have not determined the relative contributions
of the two main causes for the rise of antibiotic resistance: 1) Over
prescription of antibiotics in human medicine; 2) Use of non-therapeutic
23
levels of antibiotics in animal feeds. They maintain that relative to the
benefits of reducing food poisoning incidents, non-therapeutic levels of
antibiotics in feeds make a small contribution to antibiotic resistant infections
in humans. Quantitating the contributions of over-prescribing antibiotics for
humans versus using antibiotics in animal feeds is difficult because of the
complexity of the pathways.
2. Assume that a bill, “Preservation of Antibiotics for Medical
Treatment Act”, calling for the ban of non-therapeutic antibiotics
in animal feeds has been introduced in Congress. Pick either the
support or opposition side and write 2-3 paragraphs giving
scientifically based arguments to support your stand.
Supporters side: Using non-therapeutic levels of antibiotics
creates selective presure that allows the resistant organisms to
survive. Even if the antibiotics used in feeds are not the exact
ones used in humans, organisms can develop resistance to the
“class” of antibiotics and thus resistant to the human formulation.
Experience in the EU banned. A great deal of data supports the
conclusion that the low levels of antibiotics cause an increase in
ARB in livestock. The precautionary principle is easily applied to
this case.
Opponents side: There is no way to quantitate the relative
importance of over-prescribing human antibiotics and using nontherapeutic levels of antibiotics in feeds. Antibiotics in feeds may
be making an insignificant difference in the number of ARB. If
you cut out non-therapeutic antibiotics, you may see an increase in
animal pathogens in animals that can be transferred to humans in
the food chain. Banning antibiotics will mean more sick animals
on the farm which will require more therapeutic use of antibiotics
and also increase the cost of food for consumers.
Resources for investigation:
Pew Commission on Industrial Farm Animal Production
http://www.ncifap.org/
Union of Concerned Scientists
http://www.ucsusa.org/food_and_agriculture/science_and_impact
s/impacts_industrial_agriculture/hogging-it-estimates-of.html
EU Ban on Antibiotics
http://europa.eu/rapid/pressReleasesAction.do?reference=IP/05/16
87&format=HTML&aged=0&language=EN&guiLanguage=en
24
Farm Bureau
http://www.fb.org/index.php?fuseaction=newsroom.newsfocus&y
ear=2007&file=nr0329.html
References
Aarestrup, F.M., Seyfarth, A.M., Emborg, H., Pedersen, K., Hendriksen, R., & Badger, F.
(2001). Effect of abolishment of the use of antimicrobial agents for growth
promotion on occurrence of antimicrobial resistance in fecal enterocci from food
animals in Denmark. Antimicrobial Agents and Chemotherapy, 45, 2054-2059.
American Farm Bureau Federation. (2007). Farm bureau urges congress to keep food safe.
Retrieved August 02, 2009, from
http://www.fb.org/index.php?fuseaction=newsroom.newsfocus&year=2007&file=nr0329.ht
ml
Arias, C.A., & Murray, B.E. (2009). Antibiotic-resistant bugs in the 21st century- a clinical
super-challenge. The New England Journal of Medicine, 360, 439-443.
Ban on antibiotics as growth promoters in animal feed enters into effect. (2005, December).
Retrieved August 02, 2009, from
http://europa.eu/rapid/pressReleasesAction.do?reference=IP/05/1687&format=HTML&aged
=0&language=EN&guiLanguage=en
Center for Disease Control and Prevention, Infectious Diseases Society of America. (2003,
June) . Treatment of Tuberculosis. Morbidity and Mortality Report Weekly, 52, 1-77.
Retrived August 02, 2009, from
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5736a1.htm
Center for Disease Control and Prevention. (2006). Comunity-associated methicillinresistant Staphylococcus aureus infection amont health newborns-Chicago and Los
Angeles County, 2004. Morbidity and Mortality Weekly Report, 55(12), 329-332.
Centers for Disease Control and Prevention. (2007, October). Epidemiology and
management of MRSA in the community. Retrieved August 02, 2009, from
http://www.cdc.gov/ncidod/dhqp/MRSA_inthe_Community.html
Center for Disease Control and Prevention. (2008, July). Diseases connected to antibiotic
resisteance. Retrieved August 02, 2009, from
http://www.cdc.gov/drugresistance/diseases.htm
Center for Disease Control and Prevention. (2008, August). Antibiotic/ antimicrobial
resistance: scientific and other publications. Retrieved August 02, 2009, from
http://www.cdc.gov/drugresistance/publications.htm
Center for Disease Control and Prevention. (2008, September). National MRSA education
initiative: preventing MRSA skin infections. Retrieved August 02, 2009, from
http://www.cdc.gov/mrsa/mrsa_initiative/skin_infection/
Center for Disease Control and Prevention. (2006). Frequently asked questions about
methicillin-resistand Staphylococcus aureus (MRSA) among athletes.. Retrieved
August 02, 2009, from http://www.cdc.gov/ncidod/dhqp/ar_MRSA_AthletesFAQ.html
Center for Disease Control and Prevention. (2009, June). Get smart: know when antibiotics
work. Retrieved August 02, 2009, from http://www.cdc.gov/getsmart/campaignmaterials/week.html
Center for Disease Control and Prevention. (n.d.). MRSA educational material. Retrieved
August 02, 2009, from http://www.cdc.gov/ncidod/dhqp/ar_mrsa_ca_posters.html
25
Chambers, H.F. (2001). The changing epidemiology of Staphylococcus aureus. Emerging
Infectious Diseases, 7, 178-182.
Chambless, J.D., Stewart, P.S., & Hunt, S.M. (2005). Movie: computer model of
hypothetical persister protection of biofilms. Retrieved February 13, 2010, from the
Montana State University web site: http://www.erc.montana.edu/Res-Lib99SW/Movies/2005/05-M005.htm
Duijkeren, E., Wolfhagen, M., Box, A., Heck, M., Wannet, W., & Fluit, A.(2004,
November). Human-to-dog transmission of methicillin-resistant Staphylococcus
aureus.Emerging Infectious Diseases 10(12) Retrieved August 02, 2009, from
http://www.cdc.gov/ncidod/EID/vol10no12/04-0387.htm#cit
European Antimicrobial Resistance Servalence System. (2005). EARSS interactive database
access. Retrieved August 02, 2009, from http://www.rivm.nl/earss/database/
European Center for Disease Prevention and Control. (2009, June). European antibiotic
awareness day film. Retrieved August 02, 2009, from
http://www.channelplayer.tv/ecdctv/default.asp?p=1&lang=en-GB&assetid=1417&cid=108
European Center for Disease Prevention and Control. (n.d.). Factsheet on antibiotic
resistance. Retrieved August 02, 2009, from
http://antibiotic.ecdc.europa.eu/PDFs/EAAD_Factsheet_111108.pdf
European Surveillance of Antimicrobial Consumption. (n.d). ESAC interactive database.
Retrived August 02, 2009, from the University of Antwerp Web site:
http://www.esac.ua.ac.be/esac_service/applet/eidb.html
Florini, K., Denison, R., Stiffler, T., Fitzgerald, T., & Goldburg, R.(2005). Resistant bugs
and antibiotic drugs: State and county estimates of antibiotics in agricultural feed
and animal waste. Retrieved August 02, 2009 from the Environmental Defense Web
site: http://www.edf.org/documents/4301_AgEstimates.pdf
Food and Agriculture Organization of the United Nations, World Health Organization,
World Organization for Animal Health. (2003). Joint FAO/OIE/WHO expert
workshop on non-human antimicrobial usage and antimicrobial resistance:
Scientific assessment. Retrieved August 02, 2009, from
http://www.who.int/foodsafety/publications/micro/en/amr.pdf
Fridkin, S.K.,Hageman, J.C., Morrison, M., Sanza, L.T., Como-Sabetti, K., Jernigan, J.A., et
al. (2005). Methicillin-resistant Staphylococcus aureus disease in three
communities. The New England Journal of Medicine, 352, 1436-1444.
Goossens H., Ferech, M., Vander, R.S., Elseviers, M., ESAC Project Group. (2005).
Outpatient antibiotic use in Europe and association with resistance: a cross-national
database study. Lancet, 265 (9459), 579-587.
Grigoryan, L., Haaijer-Ruskamp, F., Burgerhof, J.G.M., Mechtler, R., Deschepper, R.,
Tambic-Andersevic, A., et al. (2006). Self-medication with antimicrobial drugs in
Europe. Emerging Infectious Diseases, 12(3), 452-459.
GroupHealth Cooperative, Tacoma/Pierce County Health Department, Washington State
Department of Health. (2006, March). Living with MRSA. Retrieved August 02,
2009, from http://www.tpchd.org/files/library/463bf2a956f3d453.pdf
Harrison, J., Turner, R., Marques, L, & Ceri, H. (2005). Biofilms. American Scientist, 93,
508-515.
House Ear Institute (2009). Video: biofilm research- Paul Webster, Ph.D. Retrieved
February 13, 2010, from the YouTube web site:
http://www.youtube.com/watch?v=XVJ6FQTIDG8
26
Humphries C. (2006). Biofilms to blame for chronic ear infections: drug-resistant
communities of bacteria pose a challenge for treatment. Retrieved February 13,
2010, from the MIT Technology Review web site:
http://www.technologyreview.com/Biotech/17150/
Infectious Diseases Society of Washington, Public Health Seattle and King County,
Tacoma/Pierce County Health Department, Washington State Department of Health.
(n.d.). Management of suspected Staphylococcus aureus skin and tissue infections.
Retrieved August 02, 2009, from
http://www.tpchd.org/files/library/37cdc74cac9cb379.pdf
Klevens, R.M., Edwards, J.R., Tenover, F.C., McDonald, L.C., Horan, T., Gaynes, R., et al.
(2006). Changes in the epidemiology of methicillin-resistant Staphylococcus aureus
in intensive care units in US hospitals, 1992-2003. Clinical Infectious Diseases, 42,
389-391.
Klevens, R, M., Morrison, M.A., Nadle, J., Petit, S., Gershman, K., Ray, S., et al. (2007).
Invasive methicillin-resistant Staphylococcus aureus infections in the United States.
Journal of the American Medical Association, 298, 1763-1771.
Kuehnert, M.J., Hill, H.A., Kupronis, B.A., Tokars, J.I., Solomon, S.L., & Jernigan, D.B.
(2006, July). Methicillin-resistant–Staphylococcus aureus Hospitalizations.
Emerging Infectious Diseases 11(6) Retrieved August 02, 2009, from the Center for
Disease Control Web site: http://www.cdc.gov/ncidod/EID/vol11no06/04-0831.htm
Labandeira-Rey, M., Couzon, F., Boisset, S., Brown, E.L., Bes, M., Benito, Y., et al. (2007).
Staphylococcus aureus Panton-Valentine leukocidin causes necrotizing pneumonia.
Science, 315, 1130-1133.
Loo, I., Huijsdens, X., Tiemersma, E., Neeling, A., Sande-Bruinsma, N., Beaujean, D., et al.
(2007, December). Emergence of methicillin-resistant Staphylococcus aureus of
animal origin in humans. Emerging Infectious Diseases 13 (12) Retrieved August 02,
2009, from the Center for Disease Control Web site:
http://www.cdc.gov/eid/content/13/12/1834.htm
Martínez, J.L. (2008). Antibiotics and Antibiotic resistance genes in natural environments.
Science, 321 (18), 365-367.
McFeters, G. (2009). A biofilm primer. Retrieved February 13, 2010, from the Biofilms
Online web site: http://www.biofilmsonline.com/cgibin/biofilmsonline/ed_intro_primer.html
National Institute of Allergy and Infectious Diseases. (2009). S.aureus bacteria. Retrived
August 03, 2009, from the National Institutes of Health Web site:
http://www3.niaid.nih.gov/news/newsreleases/aureusBacteria.htm
Oh, S. (n.d.). Antibiotics attack. Retrieved August 02, 2009, from the Howard Hughes
Medical Institute Web site:
http://www.hhmi.org/biointeractive/Antibiotics_Attack/frameset.html
Pew Commissions on Industrial Farm Animal Production. (2006). Pew commissions on
industrial farm animal production. Retrieved August 02, 2009, from
http://www.ncifap.org/
Rogers, C. (2007). How USC football tackled MRSA. Retrieved August 02, 2009, from the
American Academy of Orthopaedic Surgeons Web site:
http://www.aaos.org/news/bulletin/oct07/clinical1.asp
27
Sande-Bruinsma, N., Grundmann, H., Verloo, D., Tiemersma, E., Monen, J., Goossens, H.,
et al. (2008). Antimicrobial Drug Use and Resistance in Europe. Emerging
Infectious Diseases, 14, 1722-1730.
Smith, D.L., Dushoff, J., & Morris, J.G. Jr. (2005). Agricultural antibiotics and human
health. Public Library of Science Medicine, 2, e232.
Sørum, H., & L'Abée-Lund. (2002). Antibiotic resistance in food-related bacteria- a result of
interfering with the global web of bacterial genetics. International Journal of Food
Microbiology, 78, 43-56.
Spatuzza, A. (2002). Are we killing the cures?. Perspectives in Health Magazine (7).
Retrieved August 02, 2009, from the Tufts Web site:
http://www.tufts.edu/med/apua/Pubs/Articles/PerspectivesInHealthMaga.pdf
TecLabMktg. (2007). MRSA: the ticking time bomb v2. Retrieved August 02, 2009, from the
YouTube Web site: http://www.youtube.com/watch?v=GrySW5FeCmU
Todar, K. (2008). Bacterial resistance to antibiotics. In Todar's online textbook of
bacteriology. Retrived August 02, 2009 from
http://textbookofbacteriology.net/resantimicrobial.html
Todar, K. (2008). Colonization and invasion by bacterial pathogins. In Todar's online textbook of
bacteriology. Retrived August 02, 2009, from
http://textbookofbacteriology.net/colonization_3.html
Union of Concerned Scientists. (2001). Hogging it!: estimates of antimicrobial abuse in livestock.
Retrieved August 02, 2009, from
http://www.ucsusa.org/food_and_agriculture/science_and_impacts/impacts_industrial_agric
ulture/hogging-it-estimates-of.html
Virginia Commonwealth Unicersity. (n.d.) Super bugs- bacterial drug resistance. Retrieved
August 02, 2009, from the YouTube Web site:
http://www.youtube.com/watch?v=VQhIz2LqrYA&feature=channel_page
Vitale, C.B., Gross, T.L., and Weese, J.S. (2006). Methicillin-resistant Staphylococcus
aureus in cat and owner. Retrieved August 02, 2009, from the Center for Disease
Control and Prevention Web site: http://www.cdc.gov/ncidod/EID/vol12no12/060725.htm
Voss, A., Loeffen, F., Bakker, J., Klaassen, C., & Wulf, M. (2005, December). Methicillinresistant Staphylococcus aureus in pig farming. Emerging Infectious Diseases 11(12)
Retrieved August 02, 2009, from the Center for Disease Control Web site:
http://www.cdc.gov/ncidod/EID/vol11no12/05-0428.htm
Weese, J.S., Archambault, M., Willey, B.M., Hick, H., Hearn, P., Kreiswirth, B.N., et al.
(2005). Methicillin-resistant Staphylococcus aureus in horses and horse personnel.
Emerging Infectious Diseases 11(3) Retrieved August 02, 2009, from the Center for
Disease Prevention and Control Web site: http://www.cdc.gov/ncidod/eid/vol11no03/040481.htm
Wheelis, (2008). M. Principles of Modern Microbiology. Boston: Jones and Bartlett.