1. Microbial resistance: causes and remedy
Ranjit Pandey, chhabi lal chaudhary
CiST College, 7th
sem, B. Pham firstname.lastname@example.org
Antibiotics are those chemical compounds produced by actinomycetes, fungi, or bacteria that is
used to kill or alter the bacterial process without altering or harm to the eukaryotic host having
the infection.The emergence of antimicrobial resistance is a complex problem driven by many
interconnected factors, in particular the use and misuse of antimicrobials. Antibiotic resistance
has drastically increased in recent years in developed and developing countries and prevalence of
resistance is varies within countries between the pathogen and become the great public concern
. Bacteria that are not inhibited by normal dose schedule in minimal inhibitory concentration
range usually by achievable systemic concentration of antibiotics is called antibiotic
resistance.Antibiotic resistance occurs when bacteria evolve under selection pressure from
antibiotic use and become resistant to the medication. Because a generation for a bacterium is
extremely short (no more than one day, and often less than an hour), such evolution can occur
very quickly. The result is that existing antibiotics lose their effectiveness over time
(FDA).There are multiple mechanisms of antibiotic resistance including chromosomal mutation,
regulation of resistance gene, transfer of resistance gene etc.. Managing this problem is main
concern for the world today, find alternative medicine, decrease resistance, development of new
drugs may the long term solution to this issue.
Our research focuses current issue of antibiotics resistance, the global as well as national
problem. The resistance is increasing drastically while discovery and development of new
sensitive compound is quits low as compare to resistance rate. The chance of getting resistance is
high but difficult to discover and develop new molecules, also the great challenge for developing
country like Nepal. However minimization of resistance is better way to overcome these
problems in the world.
There are several factors like ineffective regulatory affairs; irrational drug use, absence or
passive role of pharmacist in health care system may responsible for this resistance.
We hope our research will help to health policy maker, for rationale drug use and medical
practicener to beneficial public health concern by awarding the need and responsibility with the
active participation of the pharmacist.
To describe the microbial resistance as a global as well as national problem.
To describe the mechanism of antimicrobial resistance.
To describe the potential causes of increased microbial resistance in Nepal.
To suggest the possible measures to overcome microbial resistance in Nepal
Firstly, the articles were searched from Google Scholar. After obtaining initial information the
original article and full length research article were retrieve from WHO hinari and other online
Resistance as a global as well as national problem
Resistance to antibiotics represents a worldwide health-care problem that affects therapy of
infectious diseases caused by a large variety of organisms including Gram-negative, Gram
positive bacteria or mycobacteria. The global emergence of multi-drug resistant bacterial
strains is increasing limit the effectiveness of current drugs and causing significant failure of
treatment of infections. Examples include methicillin-resistant staphylococci, pneumococci
ncomycin-rresistant topenicillin and macrolides, vaesistan enterococci as well as multidrugresistant
gram-negative organisms. The past recordof rapid, widespread and emergence of resistance
tonewly introduced antimicrobial agents indicates that even new families of antimicrobial agents
will have a short life expectancy.
Antibiotics were discovered in the middle of the nineteenth century and brought down the threat
of infectious diseases which had saved the human race. However, soon after the discovery of
penicillin in 1940, a number of treatment failures and occurrence of some bacteria such as
staphylococci which were no longer sensitive to penicillin started being noticed. Scientific
antibiotic discovery started in the early 1900s by Alexander Fleming, who observed inhibition of
growth on his agar plate on which he was growing Staphylococcus spp. It was later found that a
microorganism that was later to be called Penicilliumnotatum was the cause of the inhibition of
the Staphylococcus around it as a result of excreting some chemical into the media. That marked
the beginning of the discovery of penicillin which together with several other different
antimicrobial agents was later to save millions of humans and animals from infectious disease-
3. causing organisms.Drug-resistant strains initially appeared in hospitals, where mostantibiotics
were being used. Sulfonamide-resistant Streptoccoccuspyogenesemerged in military hospitals in
the 1930s. PenicillinresistantStaphylococcus aureusconfronted London civilian hospitalsvery
soon after the introduction of penicillin in the 1940s.Similarly,Mycobacterium tuberculosis with
resistance to streptomycin emergedin the community soon after the discovery of this
antibiotic.Resistance to multiple drugs was first detected among enteric bacteria—namely,
Escherichia coli,Shigellaand Salmonella—in the late1950s to early 1960s. Such strains posed
severe clinical problemsand cost lives, particularly in developing countries. There is an
alarming increase of antibiotic resistance of bacteria thatcause either community infections or
hospital - acquired infections. Resistance to methycillin and vancomycin is most commonly
developed in nosocomialinfections and non-hospital units. Penicillin-resistant Streptococcus
pneumoniae is frequentlydetected in pediatric units. Hospital infections with methycillin-
resistant Staphylococcusaureus occur most frequently in patients with invasive medical handling
or immunesuppressed patients with prolonged treatment in health care centers or dialysis.
In Nepal, antimicrobial resistance is a common and major problem, contributing to increased
treatment costs, hospital stay, morbidity and mortality. The resistance is more common among
Gram-negative than Gram-positive organisms. Resistance to commonly available and affordable
antimicrobials poses a major concern in the management of bacterial infection. Irrational
practices in the use of antimicrobial agents in human medicine and for prophylaxis in animal
husbandry may contribute significantly to the emergence of multidrug-resistant (MDR) strains.
Study showed that E. coli is highly resistant to ampicillin and cotrimoxazole and their sensitivity
is poor with cefotaxime as well. The other gram-ve bacilli K. pneumoniaeis mostly resistant to
cephalexin and nalidixic acid. Similarly, S. aureusis mostly resistant to ampicillin and cephalexin
in urine samples. Common pathogens of blood sample S. typhiand S. paratyphi were sensitive to
the tested antimicrobials. E. coli and S. aureusare the commonestpathogens in pus. E. coli is
highly resistant to ampicillin and is mostly resistant to cotrimoxazole. Similarly, S. aureus is also highly resistant to
As the success to develop new classes of antibiotics with novel mode of action hasbeen
compromised in the last decades, pharmaceutical companies abandoned or drasticallydecreased
investments in the antibiotic research because of resistant strains occurs sorapid for some
bacteria that clinical usefulness of theantibiotics is lost within a 5 year period.It seems that
partnerships of bigpharmaceutical companies with biotechnology organizations might be a way
to move forwardin this field. In the absence of major new classes of antibiotics, otherstrategies
have to be considered in order to minimize the development of resistance, such asthe restrictive
and educational antibiotic stewardship programmes.
4. Mechanism of antimicrobial resistance
The prevalence of drug resistance limits the therapeutic options for treatment of infections,
which some of the most effective tools treatment for the physician including antibiotics, anti-
tuberculosis and anti-malarial drugs lose their effectiveness . Antibiotic resistance occurs when
bacteria overcome the selection pressure from antibiotic use and become resistantto the
medication. Because a generationfor a bacterium is extremely short (nomore than one day, and
often less thanan hour), such evolution can occur very quickly. The result is that existing
antibiotics lose their effectivenessover time.
How do antibacterial agents work?
Most antimicrobial agents used for the treatment of bacterial infections may be categorized
according to their principal mechanism of action. There are 4 major modes of action: (1)
interference with cell wall synthesis, (2) inhibition of protein synthesis, (3) interference with
nucleic acid synthesis, and (4) inhibition of a metabolic pathway [12-14].
Table 1 Mechanisms of action of antibacterial agents
Interference with cell
β-Lactums: penicillins, cephalosporins, carbapenems,
Glycopeptides: vancomycin, teicoplanin
Bind to 50S ribosomal subunit: macrolides, chloramphenicol,
clindamycin, quinupristin-dalfopristin, linezolid
Bind to 30S ribosomal subunit: aminoglycosides,
Bind to bacterial isoleucyl-tRNAsynthetase: mupirocin
5. Interference with nucleic
Inhibit DNA synthesis: fluoroquinolones
Inhibit RNA synthesis: rifampin
Inhibition of metabolic
sulfonamides, folic acid analogues
Disruption of bacterial
All antibiotics may undergo microbial resistance due to the use and misuse of antimicrobials,
over-the-counter availability of antimicrobials without professional controls, the use of drugs of
low potency and indications or contraindications. Among these above mentioned metabolic
pathway inhibitors antibiotics are highly susceptible to resistance, if any of the drug of same
class get resistant then there will be chances of getting resistant to all of that class [15, 16].
Resistance can be described in two ways:
1) intrinsic or natural whereby microorganisms naturally do not possess target sites for the drugs
and therefore the drug does not affect them or they naturally have low permeability to those
agents because of the differences in the chemical nature of the drug and the microbial membrane
structures especially for those that require entry into the microbial cell in order to effect their
2) Resistance whereby a naturally susceptible microorganism acquires ways of not being affected
by the drug.
Acquired resistance to antimicrobials is as a result of three main strategies namely enzymatic
inactivation of the drug, modification of target sites and extrusion by efflux. While chemical
modifications could be significant in antibiotic resistance, exclusion from the cell of unaltered
antibiotic represents the primary strategy in denying the antibiotic, access to its targets and this is
believed to enhance resistance even in cases where modification is the main mechanism.
6. Figure1. Main mechanisms of bacterial resistance to antimicrobial drugs.
a) Alteration of target site
Chemical modifications in the antibiotic target may result in reduced affinity of the antibiotic to
its binding site. This is a mechanism employed by a number of pathogenic bacteria in evading
the effect of antibiotics. Modifications are usually mediated by constitutive and inducible
enzymes. Resistance to macrolides, lincosamide and streptogramin B antibiotics (MLSB
resistance) in pathogenic Streptococcus species is a result of methylation of the N6 amino group
of an adenine residue in 23S rRNA. This is presumed to cause conformational changes in the
ribosome leading to reduced binding affinity of these antibiotics to their binding sites in the 50S
ribosomal subunit. Beta-lactams antibiotics function by binding to and inhibiting the biosynthetic
activity of Penicillin Binding Proteins (PBPs), thereby blocking cellwall synthesis. In S. aureus
and S. pneumoniae, resistance to β-lactams can be a result of mutations leading to the production
of PBP2a and PBP2b respectively. The two proteins have a reduced affinity for β-lactams and
yet they take over the functions of normal PBPs in the presence of inhibitory levels of β-lactams.
This mechanism of resistance is also responsible for β-lactam resistance in non- β- lactamase
producing Haemophillus influenza [17, 18].
7. b) Enzymatic inactivation
The production of hydrolytic enzymes and group transferases is a strategy employed by a
number of pathogens in evading the effect of antibiotics. Genes that code for antibiotic degrading
enzymes are often carried on plasmids and other mobile genetic elements. The resistance to β-
lactam antibiotics by both gram negative and gram positive bacteria has long been attributed to
β-lactamases. These enzymes confer significant antibiotic resistance to their bacterial hosts by
hydrolysis of the amide bond of the fourmembered β-lactam ring. Resistance to aminoglycosides
in gram-negative bacteria is most often mediated by a variety of enzymes that modify the
antibiotic molecule by acetylation, adenylation or phosphorylation[19, 20].
b) Antibiotic efflux
It is now widely recognized that constitutive expression of efflux pump proteins encoded by
house-keeping genes that are widespread in bacterial genomes are largely responsible for the
phenomenon of intrinsic antibiotic resistance. Several studies have shown that active efflux can
be a mechanism of resistance for almost all antibiotics. The majority of the efflux systems in
bacteria are non-drug-specific proteins that can recognize and pump out a broad range of
chemically and structurally unrelated compounds from bacteria in an energy-dependent manner,
without drug alteration or degradation. The consequence of this drug extrusion is that, it leads to
a reduced intracellular concentration of the antimicrobial such that the bacterium can survive
under conditions of elevated antimicrobial concentration. The MIC of the drug against such
organisms will be higher than predicted. Multi-drug resistance efflux pumps are ubiquitous
proteins present in both gram-positive and gram-negative bacteria as either chromosomally
encoded or plasmid encoded. Although, such proteins are present constitutively in bacteria, the
continued presence of the substrate induces over-expression. This increased transcription is
responsible for the acquired resistance. In gramnegatives bacteria, the effect of the efflux pumps
in combination with the reduced drug uptake due to the double membrane barrier is responsible
for the high inherent and acquired antibiotic resistance often associated with this group of
organisms. Efflux transporters constitute about 6 to 18% of all transporters found in any given
bacterial cell . Currently, much attention is being paid towards understanding the operating
mechanisms of these pumps. This has potential applications in the design of transport inhibitors
that could be used in combination with antibiotics in development of clinically useful drugs. The
MDR pumps of pathogenic bacteria known so far, belong to five families of transporters namely;
the major facilitator super-family (MFS), the adenosine triphosphate (ATP)-binding cassette
(ABC) super-family, the small multi-drug resistance (SMR) family and the resistancenodulation-
8. cell division (RND) super-family and the multidrug and toxic compound extrusion (MATE)
family [21, 22].
Acquired resistance mechanisms can occur through various ways as described by Fluit et al.
(2001) summarized in Box 2.1 and illustrated in Fig. 2.1.
Alteration of target site
a mutation in the antimicrobial agent’ starget,
which reduces the binding of the antimicrobial
post-transcriptional or post-translational
modification of the antimicrobial agent’s target,
which reduces binding of the antimicrobial agent
reduced uptake of the antimicrobial agent
the presence of an enzyme that inactivates the
the presence of an alternative enzyme for the
enzyme that is inhibited by the antimicrobial
Antibiotic efflux active efflux of the antimicrobial agent
Potential causes of increased microbial resistance
Increasing prevalence of resistance has been reported in many pathogens over the years in
different regions of the world including developing countries. This has been attributed to
changing microbial characteristics, selective pressures of antimicrobial use, and societal and
technological changes that enhance the development and transmission of drug-resistant
organisms. Although antimicrobial resistance is a natural biological phenomenon, it often
enhanced as a consequence of infectious agents’ adaptation to exposure to antimicrobials used in
humans or agriculture and the widespread use of disinfectants at the farm and the household
levels. It is now accepted that antimicrobial use is the single most important factor
responsible for increased antimicrobial resistance [23, 25]. In general, the reasons for increasing
resistance levels include the following:
suboptimal use of antimicrobials for prophylaxis and treatment of infection,
noncompliance with infection-control practices,
prolonged hospitalization, increased number and duration of intensive care- unit stays,
multiple comorbidities in hospitalized patients,
increased use of invasive devices and catheters,
ineffective infection-control practices, transfer of colonized patients from hospital to
grouping of colonized patients in long-term-care facilities,
antibiotic use in agriculture and household chores, and
Increasing national and international travel.
9. The level of antibiotic resistance is dependent on the population of organisms that spontaneously
acquire resistance mechanisms as a result of selective pressure either from antibiotic use or
otherwise, the rate of introduction from the community of those resistant organisms into health
care settings, and the proportion that is spread from person to person.
Antibiotic can also be increased by misuse of the drugs, refer to antibiotics given in the wrong
context (e.g., for diseases that are not caused by bacteria, or bacterial infections that would get
better on their own), or at the wrong dose or for the wrong duration, is called irrational use of the
antibiotics. Exposing infectious agents to sub-inhibitory or sub-lethal concentrations of a drug
particularly favors the development of AMR.
While the contribution of each factor is difficult to quantify, the overall link between the
consumption of antibiotics and the prevalence of resistance across developing country and the
world is undisputed .
Factors contributing to the non-rational use of antimicrobials at different levels
•Self-medication (unnecessary use, inadequate dose, substandard drug quality)
• Poor adherence to regimens (medication oversight, treatment interruption)
• High need (poor underlying health, poor living conditions)
• Misperception (over-reliance on antimicrobials, inappropriate belief,
‘expensive is better’ myth)
•Poverty-associated under-treatment (inability to afford full course of
•Response to direct-to-consumer advertising by pharmaceutical manufacturers
•Lack of knowledge (inappropriate prescribing: indication, dose, route,
• Inadequate diagnosis tools (lack of accurate tests at point-of-care)
• Prescriptions in response to patient pressure
• Exaggerated fear of bad clinical outcomes (including fear of litigation)
• Economic incentives
•Absence or lack of implementation of national policies to contain AMR
(surveillance of AMR)
•Ineffective regulatory mechanisms for drug licensing and selling
(substandard drug, counterfeit)
•Control of drug supply (distribution and sales not regulated, informal sector
•Lack of hospital therapeutics committee (uncontrolled use of antimicrobials
•Lack of antimicrobial policies not updated with surveillance data and/or poor
•Lack of infection control committees, procedures or guidelines
(inadequate hygiene practices, e.g., hand hygiene)
•Lack of sterile supplies (transmission of micro-organisms via non-sterile
•Use of growth promoters in food animals
•Use of antimicrobials for treatment and disease prevention (prophylaxis,
metaphylaxis) in food animals, agriculture and aquaculture
Private industry •Industry/wholesaler/retailer pressure to sell and/or over-
Possible measures to overcome microbial resistance
The amount of antibiotics used and the speed with which resistance develops and spreads, along
with the difficulty of developing new antimicrobials, the only reasonable solution is to limit the
use of antibiotics to the necessary minimum. Although this necessary minimum is difficult to
define, many experts consider that global antimicrobial use can be greatly reduced and
optimized. The World Health Organization (WHO) defines the appropriate use of antimicrobials
as “the cost-effective use of antimicrobials which maximizes clinical therapeutic effect while
minimizing both drug-related toxicity and the development of antimicrobial resistance.
Rationalize the use of available antimicrobial agents with support of Antimicrobial
Susceptibility Testing (AST) for the prevention and containment of AMR
Regional participation in AMR as pathogens are common in the region (SAARC)
Public awareness on empirical use of antibiotics
Frequent monitoring of the laboratories involved in diagnosis
Frequent monitoring of the pathogens from hospitals and treatment centers for AMR
Multi-sectorial collaboration at human animal interface regular monitoring of the distribution
of antibiotics in the country
11. Managing the Drug Resistance Problem
1. Limiting the Spread of Drug Resistant Bacteria
Several measures could be used to prevent the spread of drug resistant bacteria. First, we could
use better treatment strategies; better immunization programs; improved hygiene and nutrition;
and initiatives targeting the poor populations. Second, it might be useful to establish antibiotic
resistance surveillance programs. Third, better education of health care professionals is required
to prevent the prescription of unnecessary antibiotics. It is noteworthy that significant investment
of time, effort, and money is necessary in order to control antibiotic resistant bacteria. Of course,
as long as antibiotics are used, antibiotics resistance is bound to occur. However, we might be
able to reduce the drug resistance problem. One strategy is to ensure that antibiotics are used
only when necessary. A second strategy is to ensure that they are used for the appropriate
amount of time; that is, that the treatment is not stopped before it is completed. Patient
compliance is a key problem in that respect. A third strategy for limiting drug resistance is to use
antibiotics combinations. Unfortunately, while all these strategies seem sound in theory, in
reality, the problem persists.
2. Development of New Antibiotics
Another possibility is to develop new antibiotics. However, that is not an easy task. The sad
irony is that many pharmaceutical companies have decided to abandon their antibiotic
development programmes when new antibiotics are needed most, since 99% of the drug
candidates fail, and antibiotics are not as profitable as other, more commonly used, drugs. he
traditional approach of screening microbes for antibiotics is not efficient. A second approach,
which utilises target-based screening, became popular when genomics tools became available.
However, although the idea is appealing, in reality, it is extremely difficult. Many companies
have tried this approach, and so far they have all failed. The whole organism-based approach is
more feasible but the conditions of screen need careful consideration [27, 28].
3. Phage Therapy
Phage therapy can also be used to deal with antibiotics resistance. This approach had already
been used by the Russians during the Second World War, and has been gaining popularity again
in recent years. Phage can be applied on the wounds of a patient to kill the bacteria, and has
proven to be quite effective. Of course, it cannot be used for internal infections, and the bacteria
might also develop phage resistance.
4. Mobilisation of Host Defence Mechanisms
Yet another approach is to mobilise host defence mechanisms. This can be achieved through the
mobilisation of innate immunity such as defensins, or through the development of vaccines,
12. which make antibiotics less necessary. The idea is to boast the immune response capability to
control the bacterial infection. Of course, that approach is not always successful.
Discussion and Conclusion
It is clear that bacteria will continue to develop resistance to currently available antibacterial
drugs by either new mutations or the exchange of genetic information, that is, putting old
resistance genes into new hosts. The development of antibiotics is among the greatest
achievements of medicine in human. History, built is clear that infection disease are still of major
medical and scientific concern. The ability of bacterial pathogen to gain resistance to new
antibiotics has been proved. Since them early Introduction of sulfonamides and penicillin’s into
clinical use. It is of great importance to rethink strategies for preventing and extending the useful
life of antibiotics such as rotating the use of antibiotics and combination antibiotics therapy.
Infectious and antimicrobial resistance is a major problem in Nepal, contributing to increased
treatment costs, hospital stay, morbidity and mortality. The resistance is more common among
Gram-negative than Gram-positive organisms, the precise extent of the problem is not known
since the majority of the published reports derive from individual units or hospitals. Resistance
to commonly available and affordable antimicrobials poses a major concern in the management
of bacterial infection. Irrational practices in the use of antimicrobial agents in human medicine
and for prophylaxis in animal may play significantly role to the emergence of multidrug-resistant
(MDR) strains. Transmission of highly resistant bacteria from patient to patient within the
hospital environment (nosocomial transmission) amplifies the problem of antimicrobial
resistance and may result in the infection of patients who are not receiving antimicrobials.
However, to minimize and control of the antibiotics resistance, several strategies should be
considered when prescribing, dispensing and use of the antimicrobial therapy for the treatment,
prevention and prophylaxis of infection and risk factors in human and animals.
A. Give the optimal antibiotic
1. Is it necessary?
2. Is the pathogen sensitive?
3. Will the drug get to the site of infection?
4. Are therapeutic concentrations achieved at the site of infection?
5. Is toxicity acceptable (risk vs. benefit?)
6. Is the therapy cost effective?
B. Administer high antibiotic loading doses for antibiotics that display concentration dependent
killing. e.g. a one-time dose for STDs or single dose daily therapy for aminoglycosides.
13. C. Stress good patient compliance - directly observed therapy for STDs & tuberculosis
D. Simultaneous therapy with unrelated antibiotics - Synergy & decreased chance of resistance.
E. Use antibiotics only when necessary -strict formulary review & use criteria
F. Place absolute limits on use of certain antibiotics e.g. quinolones, amikacin, linezolid
G. Reduce antibiotic exposure - animal feeds, self-limiting infections
H. Randomly rotate use of different antibiotics - limits continual exposure in institution
I. Use inhibitors of inactivating enzymes
In sum, many institutional, environmental, behavioral, and financial factors shape the global
antimicrobial resistance problem. Health economists and other social scientists studying health
policy should play an important role in understanding the behaviors that underlie antimicrobial
resistance and how to design incentives to coordinate a global response
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