Antibiotic Resistance: A
Review on Different
Microorganisms, Varying
Perspectives, and Control
By Adam Currie, Laila Larachi, and
Kenny Schonberger
Presented on February 18th, 2009
Introduction:
Microorganism’s resistance has increased around the world. Some bacterial organisms
that cause infections in the healthcare setting are currently resistant to all antimicrobial
agents. Bacterial resistance in community setting is also crucial in countries with limited
resources. Resistance among non-bacterial organisms is of concern, as reflected in the
widespread occurrence of primary human immunodeficiency virus (HIV) resistance2,
extensively drug-resistant tuberculosis (XDR-TB), and drug-resistant Plasmodium
falciparum malaria. These increases in the dissemination of resistance are both a medical
and public health concern since they threaten both optimal cares of patients with infection
as well as the viability of current healthcare systems2.As a result, Microorganisms
resistance is a major threat to public health and medicine. First, from the public health
perspective, drug resistance has clear effects on the patient mortality, morbidity, and
treatment cost since patients infected with resistant organisms have higher healthcarerelated costs than patients infected with non-resistant organisms due to the use of a
different antimicrobial agent which is costly and might be toxic. From the medicine
perspective, drug resistance has a clear economic impact for the medical healthcare
systems because of the increase costs associated with the increases on the prevalence of
multidrug-resistant (MDR). Human migration and “global trade” will also be an
important factor on the spread of the antimicrobial resistance across any geographic or
political boundary2. For instance, Resistant Salmonella spp.isolates was introduced to
Denmark through the importation of boar’s meat from Canada2. Examples in the United
States include the emergence of multidrug resistance in Mycobacterium tuberculosis7,
penicillin resistance in pneumocci7. The roots of the resistance are multifactorial and are
abundant while the resources to control the resistance are very limited.
Major factors that contribute to the emergence of resistance are7:
 Changes in human demographics
 Advances in technologies and industry
 Economic development
 International travel and commerce
 Microbial adaptation and change
 Deterioration in the public health infrastructure at the federal, state and local
levels in the U.S.
As a consequence, the control of the resistance will demand efforts from multiple health
and industry sectors at multinational and international level.
Mechanisms for Antimicrobial Resistance
Resistance to antimicrobial treatment has emerged as a significant barrier to the
elimination of infections since antibiotic treatment became a common treatment method
in the 1930s. There are a variety of antimicrobial mechanisms that disable or eliminate
the target microbe. For many of these mechanisms, changes in the genotype or phenotype
in multiple microbial infections has reduced or eliminated the effectiveness of the various
treatment methods.
For example, the popular antibiotic compound, penicillin, disrupts cell division by
binding to penicillin-binding proteins (PBPs). Mutations within microbes have rendered
this treatment less effective by a rate of 0 to 30%. This change occurs in two distinct
modes17. First, mutations to the PBP reduces the ability of penicillin to bind and disrupt
cell division. This change is referred to as a “tolerance” to the penicillin. In addition
changes to the membrane permeability reduce the ability of penicillin to enter the cell.
This change in the cell structure confers “resistance” to the treatment.
Another common treatment of microbial infection is the use of the
nitroimidazoles, such as metronidazole and tinidazole. This class of antimicrobial
treatment utilizes the reduction f the drug by nitroreductase and leads to damage to the
microbe’s DNA. Resistance rates for this drug are now between 20 to 95%. The
mechanism of resistance is an absence of the reduction of an intermediate compound,
imidazole. This occurs because of a reduction or abolished activit of electron transport
proteins17.
A third class of microbial resistance targets the macrolides class of microbial
treatment. Macrolides act to disable cell protein synthesis by binding to 235 rRNA.
Resistance rates for this treatment are now between 0 and 50%. The resistance
mechanism for macrolides are point mutations in the 235 rRNA genes, resulting in a
reduced ability of the drug to bind to the RNA17.
Many other classes of microbial treatments also exist, with varying mechanisms
of action including damage to DNA; inhibition of transcription, protein, ATP, and cell
membrane synthesis; reduction of proton motive force of the bacterium; and disruption of
DNA replication processes. In each of these cases, many microbes have developed ways
to avoid the disruption enough to continue multiplying. In many cases, the mechanisms
for resistance to these treatments is still unknown. These changes in the structure and
function of infectious and non-infectious microbes present significant challenges in the
treatment of infection.
Mechanisms for Antimicrobial Resistance
Several different modes of spreading resistance to antimicrobial treatments exist. The
most simple and intuitive of spreading resistance is termed “vertical transport” through
selection. Vertical transport refers to the passing of genes from one resistant microbe
through cell division and increased viability due to the benefit of resistance. While
important, vertical transport of resistance to antimicrobial treatment is not the primary
method of the spread of resistance. Rather, horizontal transfer of microbial resistance
allows microbes that have developed resistance to particular treatments to spread the
genes faster and to a more broad spectrum of microbes.
“Horizontal transfer” of resistance refers to intercellular sharing of the genes that
confer resistance to a particular antimicrobial drug. There are three main types of selftransmissible DNA elements that can be passed from one microbe to another. These are
Plasmids, transposons, and bacteriophages18. Transposons are mobile strands of DNA
that attach to certain common strings of base pairings within a strand of DNA. These can
also attach to mobile elements such as plasmids to be transferred to other cells.
Bacteriophages are frequently in the form of viruses that infect the bacteria cell and
transpose foreign DNA into the host cell’s genome. The new material occasionally causes
changes that give the cell resistance to treatments. The remainder of this section will
focus on plasmid transfer of antimicrobial resistance.
Plasmids are self contained loops of DNA that are able to copy between cells.
Most antimicrobial resistance that is transferred through horizontal means occurs by
utilizing plasmids. It has been shown in several circumstances that plasmids frequently
code for multiple drug resistant (MDR) genes18,19,20,21. The existence of MDR genes
encoded on a single plasmid can be shown to exist by comparing the transfer efficiencies
of different forms of antimicrobial resistance. In one study, the transfer efficiency for
resistance to streptomycin, chloraphenicol, tetracycline, and kanamycin were all
identical, suggesting that resistance to all four treatments were carried on one conjugative
plasmid21.
A sub-mechanism for the transfer of resistance to antimicrobial treatment is
through integrons18,21. An integron is “a site specific recombination system that
recognizes and captures mobile gene cassettes that normally encode for antibiotic
resistance. 18” Integrons can exist both on the cell’s genome, and/or on plasmids within
the cell. When the integron is located on a plasmid, it is able to transfer to other cells.
Integrons are frequently identified in cells through polymerase chain reaction (PCR) and
pulse field gel electrophoresis21. Additional information on integron regulated resistance
and transfer mechanisms is discussed in following sections.
Antimicrobial Resistance in Escheria Coli
Resistance to antimicrobial treatment has become common in several strains of
the escheria coli (e. coli) bacteria. Several studies have shown similar and startling results
on the spread of antimicrobial resistance in e. coli. One such study focuses on the transfer
of resistant genes between shiga toxin-producing e. coli (STEC) and a separate species of
e. coli18. The STEC were tested and positive for resistance to streptomycin and
suflisoxazole, which were coded on a class 1 integron, and trimethroprim and
streptothricin, which were coded on a class 2 integron.
The ability to transfer between e. coli species was tested in vitro. The results show
that resistance to antimicrobial treatment that was coded for on the class 1 integron had a
steady transfer rate18. In addition, resistance to tetracycline and oxytetracycline were
cotransfered with other antimicrobial resistance. It is most likely that the carrier plasmid
for the class 1 integron also coded for these resistances, and was transferred to the
separate species of e. coli at the same rate. The class 2 integron appears to have had no
transfer between e. coli species, as none of the antimicrobial resistance appeared in the
receiving e. coli.
A separate study aimed to show that e. coli resistance genes could transfer from
food borne pathogens to endogenous bacterial flora in vivo20. Previous studies had been
unable to show stable transfer of resistance between food borne pathogens and the host’s
own flora. Temporary transfer of resistance had been shown, but loss of acquired
resistance followed rapidly. The results of the current study showed that transfer of
resistance to antimicrobial treatment can occur in vivo, but failed to show that transfer
took place between the food borne pathogen and the local flora. Results indicated that the
transfer took place between the host’s own e. coli and a recipient cell, as the genetic
similarities of the transferred resistance gene.
Antimicrobial Resistance in Salmonella
Antimicrobial resistance in various salmonella strains is also common and
increasingly problematic. Studies range from various different strains and cover multiple
types of antimicrobial treatment. One study done in china focuses on the increase in
resistance within salmonella enterica serovar Pullorum (SESP) over the period between
1962 to 200719. Results from the study showed that:
I. High levels of resistance to ampicillin, carbenicillin, streptocycin, tetracycline,
trimethoprim, and sulfafurazole were consistant in SESP.
II. Increased resistance rates to several of these and other antimicrobial treatments
were observed over time.
III. MDR occurance rates showed high levels of increasing trends over time.
These results are consistent with the presumption that resistance to antimicrobial
treatment follow the introduction of new antimicrobial elements over time19.
A 2008 study focused on salmonella Heidelberg and resistance to microbial
treatment in humans, swine, and turkeys21. The analysis identified that resistance genes
were carried and transferred by both class 1 and 2 integrons. In swine, the majority of
salmonella Heidelberg sampled (73%) showed resistance to three different forms of
treatment. The same salmonella strain in human cultures was pan-susceptible in 80% of
the samples. The difference in the resistance that was present in swine and human strains
of the salmonella can be partially explained by the difference in the way antimicrobial
treatments are administered. Additional discussion on antimicrobial treatment to animals
is covered in following sections.
Antimicrobial Resistance in Infected Livestock and Animals
Frequently, antimicrobial resistance is prominent in microbes that colonize
livestock and other animals that receive antimicrobial treatment. Large amounts of
antibiotics are frequently used in modern food production in an attempt to reduce or
eliminate food-borne pathogens. This over-dosing of antimicrobial treatment creates an
ideal environment for the spread an persistence of resistance to antimicrobial treatment22.
This can be of especial importance since resistance to antimicrobial treatment may be
transmitted to humans via the food chain19.
Other animals, such as domesticated animals and non-food based product
livestock may have increased antimicrobial resistance as well. A 2008 study focusing on
the prudent use of antimicrobials for mink showed an increasing trend of antimicrobial
resistance among S. intermedius, e. coli, and other microbial infections23. It was also
shown that antimicrobial resistance rates were generally lower in mink than for those of
domesticated dogs. This can be explained by the less frequent use of antimicrobial
compounds on mink.
A separate study focusing on healthy dogs assayed the prevalence of
antimicrobial resistance in e. coli and enterococcus spp24. The results of the investigation
showed significant association between recent antimicrobial treatment in dogs and
resistance in both microbes. The study also reported for the first time the appearance of
ampicillin resistant Enterococcus faecium in dogs. This discovery provides additional
evidence that antimicrobial resistance continues to emerge as new treatments are
introduced. The first contact with resistance of this kind is important to both animal and
human health, and the researchers recommend further investigation on the prevalence of
AREF in dogs.
Antibiotic Resistance in Different Parts of the World
Global Perspective
Antibiotic resistance is a major issue when it comes to global health8. Infectious
diseases in all parts of the world have shown signs of antimicrobial resistance. For
example, strains of Streptococcus pneumoniae (S.s pneumoniae) have been found all over
the world (see figure KX.1 below). Part of the global problem with antimicrobial
resistance is increased population growth, trade, and travel have increased and caused the
spread of many strains of resistance8. Trade and travel has allowed for must faster spread
of antimicrobial resistant pathogens through the transportation of infected people and
food which has been genetically modified or contains antibiotic resistant microorganisms
between countries.15 Global travel has become such an issue that “visitors to developing
countries acquire antibiotic-resistant E. coli [(Escherichia coli)] as part of their normal
flora.”14 Travelers then serve as vectors and can spread antibiotic-resistant E. coli when
they return to their home countries. Obviously, population growth has led to an increase
in the number of people who become sick and need treatment. The use of antibiotics on
such people has helped lead to the increase of antimicrobial resistance strains of
pathogens.
Figure KX.1. Percentage of S. pneumoniae resistant to multiple antiobiotics9
Cooperation between countries is key to preventing the global spread of
antimicrobial resistant strains8. The World Health Organization (WHO) plays a major
role in uniting countries internationally around the world to help improve global health,
including dealing with antibiotic resistant microorganisms. In 2001, WHO published a
report on Global Strategy for Containment of Antimicrobial Resistance. In the report,
recommendations are given , such as “improving access to and use of antimicrobials,
strengthening surveillance capabilities and other aspects of healthcare systems, enforcing
regulations, and developing new preventative and therapeutic medications”8. Although
many of these recommendations aren’t an issue in developed countries, they tend to be
major issues in developing countries.
There is a strong correlation on a nationwide basis between antimicrobial
resistance and antibiotics use. Countries which use more a antibiotics on a per capita
basis tend to have higher percentages of resistant bacteria. Penicillin-nonsusceptible S.
pneumoniae is a perfect example of this. Countries which use more antibiotics have a
higher percentage of penicillin-nonsusceptible S. pneumoniae, and countries which use
less antibiotics have a lower percentage of penicillin-nonsusceptible S. pneumoniae (see
figure KX.2).
Figure KX.2. Antibiotic Usage vs. Percentage of Resistant S. pneumoniae.12
Developing Countries
Antimicrobial resistance is a major public health issue in developing countries
and is increasing in developing countries9. This is due to increased global trade and
travel as well as due to poverty and inadequate resources in undeveloped countries8,9.
Poverty and inadequate resources are the main causes of poor sanitation, hunger,
starvation, poor access to drugs, and poor healthcare delivery in developing countries8,9.
Poor sanitation is the cause of increased antimicrobial resistance in many
developing countries. Many residents of developing countries drink water from sources
which are also used to dispose of wastewater. In addition, studies by the U.S.
Environmental Protection Agency (EPA) have shown “antibiotic resistance genes may
pass from fecal bacteria may pass into environmental bacteria and serve as a reservoir of
resistance” so other bacteria can acquire the resistance.13 Hence, the residents of these
countries are drinking water with antibiotic resistant bacteria which further facilitates the
spread of these genes to microorganisms the residents are commonly subjected to which
can then easily spread to infectious diseases which communities in these countries are
subjected to.
Another issue poverty brings to developing countries is hospitals are not
commonly accessible to all residents. Hence, healthcare facilities are inaccessible to
many residents in developing nations, especially in rural areas of these countries8,11.
However, this does not stop residents from obtaining medications they may or may not
need to treat diseases they have. In fact for many residents, healthcare providers are not
their first point of contact.8
Many residents turn to “unsanctioned stall keepers, itinerant vendors, hawkers,
and purveyors of other materials” as their first point of contact for obtaining drugs to cure
diseases.8 This lack of control of regulations in developing countries has proven to be a
major issue for many reasons. First of all, patients can never be 100% they know what
they are taking. They may be putting themselves in serious risk by taking medications
from these sources. In addition, many of these drug vendors are not good sources for
drug treatment advice.8
Even when proper access to healthcare facilities is available, unnecessarily taking
antibiotics can still be an issue. Many healthcare providers in developing nations will
prescribe antimicrobials even when they are unneeded. This is in part due to improperly
trained medical professionals, but it is primarily done for financial gains since many
practices are operated on the foundation of profit8. This is obviously an example of the
abuse of antibiotics which is fairly common in developed countries. Studies have shown
antibiotic “resistant organisms are more likely to be encountered in urban than in rural
settings”9. This is because of the abuse of antibiotics that takes place in urban settings in
developing countries. The ability to obtain medications from unknowledgeable sources
as well healthcare providers improperly prescribing medications are the main contributors
to the abuse of antimicrobials in urban settings of developing countries.
Taking improper doses of antimicrobials is also a problem in developing
countries. Taking inappropriate doses of antibiotics is often ineffective at treating
illnesses if the dose is too small. In addition, taking smaller than needed doses may also
lead to the development of antimicrobial resistance in pathogens10. This is because
“lower-than-stated doses will produce suboptimal levels of the circulating drug, which
could result in selection of drug-resistant strains [in addition to ] therapeutic failure” (see
figure KX.3 below)8. Taking inappropriate doses of antibiotics can be due to purchasing
antibiotics from unknowledgeable sources, but it can also be due to the use of expired
antibiotics and/or self-diagnosis10,9,8. Many people in developing countries will store
unused antibiotics after they have overcome the illness. They may use the antibiotic later
on if they become ill again8. At this point, the antibiotic is most likely expired and the
strength of it is greatly diminished. Hence, doses from the antibiotic are not as strong as
they originally were. This greatly diminishes the ability of the antibiotic to cure a
pathogen. In addition to this, it is also common practice to use antibiotics which are
stored past expiration may on family members. Approximately 60% of Chinese parents
follow this practice, and more than 50% of the time, the correct antibiotic is not even
used8.
Figure KX.3. Depiction of how taking improper doses of antibiotics may benefit microorganisms 10.
Developed Countries
Developed countries generally face different conflicts with the development and
spread of antimicrobial resistance genes than developing countries do. In most developed
countries, there are well established organizations to help prevent and control the spread
of diseases, including preventing the development and expansion of microorganisms
which are drug resistant. In the U.S., these organizations include national government
agencies, such as FDA (Federal Drug Administration) and CDC (Centers for Disease
Control and Prevention), and local government agencies, such as state, county, and city
health departments.
Government agencies in developed countries help deal with the issue of improper
or self-medicating of antibiotics by instituting prescription-only regulations8 Hence,
antibiotics in these countries can only be legally obtained with a prescription from a
doctor. In addition to this, regulations are generally followed more stringently in
developed countries which helps to reduce the abuse of antibiotics.8
One of the major issues facing developed countries is the import of antimicrobial
resistant genes from developing countries. In US, “the number of [Vibrio cholerae]
isolates resistant to at least one agent rose from 3% in 1992 to 93% in 1994. 9”
One of the major contributors to this problem is the poor sanitation in developing
countries, as discussed previously. To help combat the import of resistant genes,
government agencies in developed countries often require infected individuals be isolated
until they are no longer contagious before being re-admitted to the country.
Another major problem concerning the development of resistant genes in
developing countries is antibiotics are usually readily available. Not only does their use
on humans result in result in higher rates of antimicrobial resistance, as discussed
previously, but their use in agriculture does as well. In the U.S., antimicrobials are
sprayed on fruit trees to help protect them from microbes9. However, this practice also
contributes to the spread of antimicrobial resistance in the U.S., as well as any countries
the fruit is shipped to. In addition, the increase in antibiotic resistant genes in developed
countries requires further research be done to continue to produce new antibiotics to help
fight pathogens. This causes cost to be a major burden on developed countries for
righting resistant pathogens.16 It is estimated up to $18.6 million has been spent on
medicating resistant pathogens in outpatients alone.9 This does not include the cost of
medicating inpatients with resistant pathogens or to research new antibiotics.
Methods used for the control of resistance:
Infectious diseases are major threats to the humanity worldwide. Several groups of
organisms have emerged as significant cause of mortality and morbidity for the last two
decades and threaten to increase in the future. Bacteria that are refractory to treatment
because of the development of resistance were among these organisms. The control of the
resistance is a very complex process since it depends on combined efforts within the
local, regional, national and international agencies since the spread of the resistance has
no geographic boundaries2. These efforts are similar regardless of the type of infectious
disease being controlled. However, some of the specific actions required for the control
of certain resistant organisms may differ from those required to control others2.
1. Strategies for minimizing resistance focus on efforts at several different levels
of responsibility from provider to international agencies:
Several forces have been involved in the influence of antimicrobial resistance rates. The
main driving force is the ecological pressure obtained from the use of animal or human
antimicrobial2, whereas spread is caused by the transmission of resistance both at the
community and healthcare levels2.

Role for providers:
Healthcare providers can develop and updates educational programmes to educate
patients about the route of transmission, behaviors to minimize the spread of the
infection, and also their adherence with medications to avoid the emergence of
resistance2.

Role of local health departments and healthcare facilities:
Monitoring and management of programmes for antimicrobial resistance should
be based on the local level since regions may differ greatly in their practices, policies and
problems. Local health departments and healthcare facilities participate by different ways
in education, generating useful tools and disseminating them to providers and patients6.
These organizations could facilitate the accessibility to providers of susceptibility testing
which in turn will enhance the implementation of surveillance programmes of multidrugresistant organisms2.Healthcare facilities should provide administrative support and basic
infrastructure for laboratory diagnosis and infection control. Reporting of resistance
summaries to providers, the community and the regional health officials also provides
opportunities for promoting behavior change and guideline adherence2.

Role for regional, national and international health organization:
These groups have responsibilities in the effort to control resistance since they often
aggregate, summarize and disseminate surveillance reports2. International agencies often
promote the development of comprehensive guidelines for antimicrobial use. For
instance, guidelines for the management of multidrug-resistant tuberculosis and
extensively drug-resistant tuberculosis assist in the detection and management of
individual cases, the prevention of spread, the tracing of contacts and the regulation of
medication manufacturing and distributing practices2.
2. Responses that might be appropriate according to the resources available for
control, focusing on limited-resource settings:
Antimicrobial resistance is a cause and consequence of resource utilization. Because of
that, forces that cause the emergence and spread of resistance are different depending to
the different levels of resource limitation. Similarly, the public health consequences and
the appropriate policy responses are different for each case.

Settings with optimal resources:
The excess resistance and costs derived from the antimicrobial use are justified since
deaths from infection are being prevented by the rational use of antimicrobials2. The
benefit derived from antibiotic use outweighs the risks of emerging resistance.
Appropriate response would be the drug development: vaccine, diagnostics, and
surveillance.

Setting with minimal resources:
Occurs in poor countries where resistance can be caused by the inadequate treatment
in which patients will be able to obtain only a few doses of an antimicrobial agent.
However, when the resource limitation is extreme, few antimicrobials are available and
minimal resistance may emerge as a natural response to selective pressure resulting from
use2. As a consequence, Excessive death due to treatable infections by antimicrobial
agents which will cause an excessive public health cost. Appropriate response might be to
scale-up antimicrobial use while incorporating surveillance, vaccination and infection
control activities at the same time.

Settings with extreme to moderate resource limitation:
Predominates in many developing countries and in some rural and community centers
of the developed world. Excessive emergence of resistance due to the inappropriate use
of the antimicrobial agents because of the interrupted supply, improper dosing, use of
counterfeit drugs and scarcity of regulations regarding antimicrobial purchase2. As a
consequence, excessive mortality, and healthcare costs. Appropriate response will be to
optimize appropriate and consistent use of good-quality antimicrobials.

Settings with minimal to moderate resource limitation:
This scenario predominates in the developed world and in high-complexity centers in
the developing world. Excessive emergence of resistance due to the excessive use of
antimicrobials, and the use of broad-rather than narrow-spectrum agents. The appropriate
response will be the optimization of antimicrobial use.
3. Approach to the control of the emergence of resistance:

The use of antibody therapy to control drug resistance:
“The use of antibody-based therapy for resistant organisms is especially appealing in
view of the increasing rates of drug resistance among common microbial species, such as
S.pneumoniae, S.aureus and commensal microbes such as C.albicans and enterococci.
Moreover, an alternative therapeutic modality may alleviate antimicrobial agentassociated selection for drug resistant mutant. An example of this approach is provided
by the successful use of specific IG to combat methicillin resistant S. aureus in Russia3.”
These antibodies are stable, robust products that have a longer half-life than most drugs,
allowing convenient dosing regimens3. There advantages consist of their pathogenspecificity and versatility. However, the disadvantages consist of the need of parental
administration, the risk of hypersensitivity reactions, immune complex-mediated
complications of their use and also their high associated cost.

Body Substance Isolation(BSI):
It is widely used approach for the control of resistant organisms in the US which
is based on universal application of stringent barrier techniques in the care of all patients
whose wounds, mucous membranes, secretions, and excretions must be handled,
regardless of whether the patients are known to be colonized or not6.

Antimicrobial cycling:
Deliberate removal and substitution of specific antimicrobials or classes of
antimicrobials within an institutional environment to avoid or reverse the dissemination
of antimicrobial resistance5. True antimicrobial cycling requires a return to the
antimicrobial that was first used. The duration of these cycles may be determined on the
basis of the local microbiologic flora or a preset time period. The goal of the cycling is to
reduce the current resistance and prevent the emergence of new resistance. However, the
efficacity and consequences are not well known.
Current techniques used for resistance control in hospitals4:

Reducing the rate of antibiotics consumption.

Reducing the overall rate of transmission of bacteria between patients by
promoting hand washing, and other infection control procedures.

Increasing the rate at which patients leave the hospital-the rate of turnover.

The use of antibiotics for which there is little or no resistance.
These methods will not be efficace because the control of resistance in this closed
environment relies on the success of the resistance control in the community.
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