Antimicrobial resistance has developed as a serious threat due to overuse and misuse of antibiotics. Key bacterial infections like pneumonia, meningitis and tuberculosis are showing resistance to first-line drugs. This results in prolonged illness, higher mortality and increased healthcare costs to use second and third-line drugs. Resistance develops through genetic mutations and transfer of genes between bacteria. Improving antibiotic use can help control the emergence and spread of resistance.

1. DEVELOPMENT OF
ANTIMICROBIAL
RESISTANCE AND ITS
PREVENTION
Soumya Ranjan Parida
Basic B.Sc. Nursing 4th
year
Sum Nursing College

2. INTRODUCTION
Since discovery during the 20th century, antimicrobial
agents have substantially reduced the threat posed by
infectious diseases.
The use of these "wonder drugs", combined with
improvements in sanitation, housing, and nutrition, and
the advent of wide­spread immunization programmes, has
led to a dramatic drop in deaths from diseases that were
previously widespread, untreatable, and frequently fatal.
Over the years, antimicro­bials have saved the lives and
eased the suffering of millions of people. By helping to
bring many serious infectious dis­eases under control,
these drugs have also contributed to the major gains in life
expectancy experienced during the latter part of the last
century.

3. These gains are now seriously jeopardized by another
recent development: the emergence and spread of
microbes that are resistant to cheap and effective first­
choice, or "first­line" drugs.
 The bacterial infections which contribute most to
human disease are also those in which emerging and
microbial resistance is most evident: diarrhoeal
diseases, respira­tory tract infections, meningitis,
sexually transmitted infec­tions, and hospital­acquired
infections
 Some important ex­amples include penicillin­resistant
Streptococcus pneumoniae, vancomycin­resistant
enterococci, methicillin­resistant Sta­phylococcus
aureus, multi­resistant salmonellae, and multi­resistant
Mycobacterium tuberculosis. The development of
resistance to drugs commonly used to treat malaria is of
particular con­cern, as is the emerging resistance to
anti­HIV drugs.

4. Consequences
The consequences are severe. Infections caused
by resistant microbes fail to respond to treatment,
resulting in prolonged illness and greater risk of
death.
 Treatment failures also lead to longer periods of
infectivity, which increase the numbers of
infected people moving in the community and
thus ex­pose the general population to the risk of
contracting a resistant strain of infection.

5. When infections become resistant to first­line
antimicrobials, treatment has to be switched to second­
or third­line drugs, which are nearly always much more
expensive and sometimes more toxic as well, e.g. the
drugs needed to treat multidrug­resistant forms of
tuberculosis are over 100 times more expensive than the
first­line drugs used to treat non­re­sistant forms.
 In many countries, the high cost of such replace­ment
drugs is prohibitive, with the result that some diseases
can no longer be treated in areas where resistance to first­
line drugs is widespread.
Most alarming of all are diseases where resistance is
developing for virtually all currently available drugs, thus
raising the spectre of a post­antibiotic era.
 Even if the pharmaceutical industry were to step up
efforts to develop new replacement drugs immediately,
current trends suggest that some diseases will have no
effective therapies within the next ten years.

6. Causes
Microbes cause infectious diseases, and antimicrobial
agents, such as penicillin, streptomycin, and more than 150
others, have been developed to combat the spread and
severity of many of these diseases.
 Resistance to antimicrobials is a natural biological phe­
nomenon that can be amplified or accelerated by a variety of
factors, including human practices.
The use of an antimicrobial for any infection, real or feared,
in any dose and over any time period, forces microbes to
either adapt or die in a phenomenon known as "selective
pressure". The microbes which adapt and survive carry genes
for resistance, which can be passed on.

7. Bacteria are particularly efficient at enhancing the effects
of resistance, not only because of their ability to multiply
very rapidly but also because they can transfer their
resistance genes, which are passed on when the bacteria
replicate.
 In the medical setting, such resistant microbes will not be
killed by an antimicrobial agent during a standard course
of treat­ment.
Resistant bacteria can also pass on their resistance genes
to other related bacteria through "conjugation", whereby
plasmids carrying the genes jump from one organism to
an­other.
 Resistance to a single drug can thus spread rapidly
through a bacterial population. When anti­microbials are
used incorrectly ­ for too short a time, at too low a dose, at
inadequate potency; or for the wrong disease ­ the
likelihood that bacteria and other microbes will adapt and
replicate rather than be killed is greatly enhanced.

8. Much evidence supports the view that the total
consumption of antimicrobials is the critical
factor in selecting re­sistance.
Paradoxically, underuse through lack of access,
inadequate dosing, poor adherence, and
substandard anti­microbials may play as
important a role as overuse.
 For these reasons, improving use is a priority if
the emergence and spread of resistance are to be
controlled.

9. MECHANISM OF ANTIMICROBIAL
RESISTANCE
INACTIVATING ENZYMES
These enzymes degrade antibiotics such as
aminoglycodies inactivating enzymes, beta
lactames, chloramphenicol acetyl transferase.
Aminoglycosides such as gentamicin, amikacin,
netilmicin and tobramycin are broad spectrum
antimicrobials used to treat infections caused by
aerobic gram negative bacilli.
The most common mechanism of resistance to
aminoglycosides is through producing
aminoglycoside modifying enzymes that
inactivate the drugs.

10. ALTERATION OF THE TARGET SITE
Structural modification result in a lower affinity
of the target site for the antibiotics so that the
antibiotic binding to the target is decreased or
totally eliminated.
For penicillin resistance in streptococcus
pneumoniae the mechanism involves alteration in
one or more of the penicillin binding protien.
MRSA which codes for an altered penicillin
binding protein renders all beta lactames
ineffective.

11. ALTERATION OF BACTERIAL CELL MEMBRANE
There is a structural difference between the cell walls of
gram positive and gram negative organism.
Gram positive have a single cell membrane with external
layer of peptidoglycan.
Gram negative bacteria posess an inner plasma membrane
and outer cell membrane includes lipopolysaccharides
which tightly bound hydrocarbon molecule, which
impede hydrophobic substances like erythromycin and
nafcillin.
Porin proteins- are arrange to form water filled diffusion
channel through which antibiotics traverse.

12. Negatively charged molecules move slowly across the
membrane than the more positively charged
molecules.
Beta lactams with buly side chains such as
piperacillin and cefaperazone cross the membrane
poorly.
Resistance to imipenem is by decreased permeability
through this porin channel.

13. ANTIBIOTIC EFFLUX
In some bacteria an important mechanism of
resistance is active removal of antibiotics from the
bacterial cell so that intracellular concentration of
antibiotics never reach a sufficiently high level to
exert antimicrobial activity.
This efflux mechanism is energy depandant this is
a prime defense for bacteria against tetraclines,
macrolids and meropenum.

14. Key factors in emergence of resistance
The emergence and spread of multiply resistant organisms
represent variety of factors that include mutations in
common resistance genes that extend their spectrum of
activity;
 the exchange of genetic information among
microorganisms in which resistance genes are transmitted
to new hosts;
 the development of environmental conditions in hospitals
and communities (selective pressures) that facilitate the
development and spread of resistant organisms;
 the proliferation and spread, in some cases globally, of
multiply resistant clones of bacteria;
 and the inability of some laboratory testing methods to
detect emerging resistance phenotypes

15. Genetic exchange.
The ability of bacteria to exchange genetic information by
a variety of mechanisms has been recognized for >40
years.
 The most commonly recognized modes of exchange are
transformation and transduction (among gram-positive
organisms), and conjugation (among gram-negative
organisms).
 Among gram-negative organisms, plasmid transfer among
a variety of enteric bacilli led to prolonged outbreaks of
multiresistant organisms in hospitals.
 More recently, the acquisition of multidrug resistance
plasmids by strains of Vibrio cholerae and Shigella
dysenteriae has made control of diarrheal disease and
dysentery difficult in many African countries

16. The ability of gram-positive organisms to exchange DNA
via conjugation is often overlooked by microbiologists;
however, it is a very effective means for transmitting
antimicrobial agent resistance genes among organisms.
 The sharing of aminoglycoside resistance genes among
several species of staphylococci and enterococci is one
example of an active pathway.
 Genetic exchange pathways also exist between gram-
positive and gram-negative organisms in which the
transfer of kanamycin resistance genes has been observed.

17. Enterococci provide an excellent example of how
organisms can accumulate resistance genes by
genetic exchange and develop into multidrug-
resistant pathogens.
 The first vancomycin-resistant enterococci (VRE)
were reported in the United States in 1989; most
were recovered from patients in intensive care
units.
 In 1996, the percentage of VRE isolates in
intensive care units approached 14%, and many of
these were also resistant to ampicillin,
gentamicin, and streptomycin, leaving few
therapeutic options.
.

18.  Most of the resistance determinants in these
multiresistant strains were borne on mobile plasmids and
transposons.
 The genetics of enterococcal resistance to glycopeptides is
complex and involves a number of unique determinants.
In addition to the vanA (high-level), vanB (moderate-
level), and vanC (low-level, intrinsic resistance)
determinants in enterococci, 2 novel determinants were
recently described. The vanD determinant was first
recognized in New York City in 1990 and has subsequently
been recognized in a Boston medical center

19. Initially, VRE appeared primarily in animals in Europe, but
in the United States it appeared almost exclusively in
hospitalized patients.
 Infections with VRE in humans are emerging throughout
the world. VRE now appear to be present in all 50 states in
the United States and in Europe, South America, South
Africa, Australia, and Taiwan .
Just as the organisms have disseminated, so have the
resistance genes also migrated to other species and genera.
The vanA determinant has been detected in Oerskovia
turbata, Arcanobacterium haemolyticum, and Bacillus
circulans, and the vanB gene has been detected in
Streptococcus bovis.
The transfer of the vanA gene from E. faecalis to S. aureus
has been accomplished in the laboratory, but naturally
occurring isolates of S. aureus with high-level vancomycin
resistance have yet to be recovered from humans or
animals.

20. Selective pressures in health care and
community settings
Selective pressure refers to the environmental conditions that
enhance the ability of bacteria to develop resistance to antimicrobial
agents and to proliferate.
 This ability to survive may be the result of acquisition of new DNA
(as is often the case with VRE) or it may be due to spontaneous
mutation, as is often the case for rifampin-resistant organisms.
 Expanded use of antimicrobial agents in hospitals and in sites outside
the hospital increases the selective pressure for resistant organisms to
emerge in these settings.
 The intensity of use of antimicrobial agents appears to be
proportional to the resistance levels in organisms in hospital settings.
 Recent studies have shown that, among staphylococci, enterococci,
and pseudomonads, levels of resistance are highest in organisms from
patients in intensive care units (where use of antimicrobial agents is
highest) but are lower in patients from other wards in the hospital
and are even lower in outpatient settings

21. Selection of resistance in bacteria can occur in a variety of
ways. In a study reported by Rasheed et al., one strain of E.
coli that was isolated, on multiple occasions, from the
blood samples of a young girl with aplastic anemia was
originally noted to carry a TEM-1 β-lactamase.
 During therapy with extended-spectrum cephalosporins,
the organism acquired an SHV-1–type β-lactamase that,
because of hyperproduction, began to manifest resistance
to ceftazidime and other extended-spectrum
cephalosporins.
 A spontaneous mutation in the SHV-1 β-lactamase led to
the development of a novel SHV-8 variant with enhanced
ceftazidimase activity, increasing the ceftazidime MICs
from 16 μg/mL to >64 μg/mL.
This was the result of a single amino acid change from
aspartate to asparagine at position 179. Simultaneously,
the organism lost 1 of its porins (outer-membrane
channels), thus becoming resistant to cephamycins (i.e.,
cefoxitin and cefotetan).
 All these changes occurred within 3 months while the
child was undergoing multiple courses of anti-infective
chemotherapy.

22. Detection of Resistance to Antimicrobial Agents
in the Clinical Laboratory
Decreased susceptibility to vancomycin in S. aureus can be
difficult to detect in the laboratory. Disk diffusion does not
differentiate vancomycin-susceptible strains from those with
increasing resistance;
however, use of vancomycin agar screening plates made with
either Brain Heart Infusion agar or Mueller-Hinton agar works
well.
 This is one of several examples of novel resistance phenotypes
that are difficult to detect using traditional antimicrobial agent
susceptibility testing methods.
During the past several years, various proficiency testing
studies, including those conducted by the Centers for Disease
Control and Prevention (CDC) and the College of American
Pathologist, have highlighted the difficulties that laboratories
experience in detecting several of the newer bacterial resistance
mechanisms with current laboratory methods

23. Data from proficiency testing studies conducted by the
CDC suggest that laboratories not only have difficulty
detecting ESBL-producing strains, but often do not follow
National Committee for Clinical Laboratory Standards
(NCCLS) guidelines regarding the appropriate
antimicrobial agents to test and report.
 For example, 6 of 38 laboratories did not test an
extended-spectrum cephalosporin or aztreonam against
gram-negative bacilli reported to be isolates from blood
cultures.
Perhaps the most difficult phenotypes to detect are
decreased susceptibility to β-lactams in pneumococci and
decreased susceptibility to vancomycin in staphylococci

24. Clinical laboratories must be constantly aware of changes
that occur in the susceptibility patterns of pathogenic
microorganisms.
However, growing restraints on the personnel and supply
budgets in hospital-based microbiology laboratories may
hinder the widespread implementation of the newer tests
that improve detection of these novel phenotypes.
 In fact, newer MIC testing systems often use only 1–3
dilutions of a drug to determine resistance.
Often the highest dilution tested on commercially
prepared test panels is only in the intermediate range.
 These breakpoint panels eliminate important quantitative
information, such as the actual MICs of antimicrobial
agents, and result in a report that lists only the
interpretive categories of susceptible, intermediate, and
resistant.
Thus, the ability to monitor the gradual increase in MICs
of a particularly species over time is lost.

25. Circulation of Multiply Resistant Bacterial Clones
The final issue of importance is the development and global
spread of multiply resistant bacterial pathogens.
 In the past, multidrug resistance was often equated with
decreased virulence; however, loss of virulence clearly has not
occurred with several globally disseminated strains of
pneumococci and S. aureus.
The serotype 23F Spanish clone of S. pneumoniae, which is
resistant to penicillin, chloramphenicol, tetracycline, and
trimethoprim-sulfamethoxazole, and the serotype 6B isolate,
which originated in Spain and spread throughout Iceland in the
early 1990s, are 2 examples of multiresistant organisms that
maintained their virulence.
 In the United States, the Spanish 23F clone was noted as a
cause of infections among children who attended a day care
center.
Some isolates of this clone have been reported to have acquired
resistance to cefotaxime and erythromycin in addition to its
already established multidrug resistance profile

26. Another example of a highly virulent, multidrug resistant
clone was the trans-Canadian spread of a single clone of
methicillin-resistant S. aureus that was introduced into a
small hospital in Canada via a patient who arrived from
India with dermatitis.
Although the patient spent only 4 h in the hospital, 4
cases of nosocomial methicillin-resistant S. aureus were
linked to the patient in that institution.
 An additional 21 cases were observed in a Vancouver
hospital to which the patient was transferred, and 26 cases
were observed in a Manitoba hospital where the patient
also was admitted

27. Factors that encourage the spread of
resistance
The emergence and spread of antimicrobial
resistance are complex problems driven by
numerous interconnected fac-tors, many of which
are linked to the misuse of antimicrobi-als and
thus amenable to change.
 In turn, antimicrobial use is influenced by an
interplay of the knowledge, expectations, and
interactions of prescribers and patients, economic
in-centives, characteristics of a country's health
system, and the regulatory environment.

28. Patient-related factors are major drivers of
inappropriate antimicrobial use. For example,
many patients believe that new and expensive
medications are more efficacious than older
agents.
 In addition to causing unnecessary health care
expenditure, this perception encourages the
selection of re-sistance to these newer agents as
well as to older agents in their class

29. Self-medication with antimicrobials is another
major factor contributing to resistance. Self-
medicated antimicrobials may be unnecessary, are
often inadequately dosed, or may not contain
adequate amounts of active drug, especially if they
are counterfeit drugs.
 In many developing countries, antimi-crobials
are purchased in single doses and taken only until
the patient feels better, which may occur before
the patho-gen has been eliminated.
 Inappropriate demand can also be stimulated by
marketing practices. Direct-to-consumer
advertising allows pharmaceu-tical manufacturers
to market medicines directly to the public via
television, radio, print media, and the Internet.
 In par-ticular, advertising on the Internet is
gaining market pen-etration, yet it is difficult to
control with legislation due to poor enforceability.

30. Prescribers' perceptions regarding patient expectations and
demands substantially influence prescribing practice. Physi-
cians can be pressured by patient expectations to prescribe
antimicrobials even in the absence of appropriate
indications.
 In some cultural settings, antimicrobials given by injection
are considered more efficacious than oral formulations.
 Such perceptions tend to be associated with the over-
prescribing of broad-spectrum injectable agents when a
narrow-spec-trum oral agent would be more appropriate.
 Prescribing “just to be on the safe side" increases when
there is diagnostic uncertainty, lack of prescriber knowledge
re-garding optimal diagnostic approaches, lack of
opportunity for patient follow-up, or fear of possible
litigation.
In many countries, antimicrobials can be easily obtained in
pharmacies and markets without a prescription

31. Hospitals are a critical component of the antimicrobial re-
sistance problem worldwide. The combination of highly
sus-ceptible patients, intensive and prolonged
antimicrobial use, and cross-infection has resulted in
nosocomial infections with highly resistant bacterial
pathogens.
 Resistant hospital-acquired infections are expensive to
control and extremely dif-ficult to eradicate.
 Failure to implement simple infection control practices,
such as handwashing and changing gloves before and after
contact with patients, is a common cause of infection
spread in hospitals throughout the world.
 Hospi-tals are also the eventual site of treatment for
many patients with severe infections due to resistant
pathogens acquired in the community.
 In the wake of the AIDS epidemic, the preva-lence of such
infections can be expected to increase.

32. Veterinary prescription of antimicrobials also contributes
to the problem of resistance. In North America and
Europe, an estimated 50% in tonnage of all antimicrobial
production is used in food-producing animals and poultry.
 The largest quantities are used as regular supplements for
prophylaxis or growth promotion, thus exposing a large
number of animals, irrespective of their health status, to
frequently subtherapeutic concentrations of
antimicrobials.
Such wide-spread use of antimicrobials for disease control
and growth promotion in animals has been paralleled by
an increase in resistance in those bacteria (such as
Salmonella and Campylobacter) that can spread from
animals, often through food, to cause infections in
humans.

33. STRATEGIES TO COMBACT ANTIMICROBIAL
RESISTANCE
Physicians education and awarness to prevent misuse
of antibiotics.
Rigorous adherence to infection control guidelines.
Reducing the use of antibiotics with high potential
for resistance and rotating them with low potential
resistance drugs.
Good antibiotics stewardship with antibiotic policies
that work.

34. Eliminating inappropriate therapy for ‘look alike’ non
infectious clinical syndromes that mimic sepsis.
De-escalation of broad spectrum antibiotic therapy
once sensetives are in.
Optimising adequate antibiotic dosing.
Discouraging antibiotic weaning.

35. THANK YOU.