Antibiotics al., 2014). And hence this condition

Antibiotics
are a lifesaving agent which are used to target several against several pathogenic
bacteria. However, development of antibiotic resistance mechanisms by bacteria are
creating conditions where these, once life-saving drugs, no longer effectively
works out. Antibiotic resistance is the global upsetting trend and a
challenging problem for researchers from all fields worldwide.

 

Among many
antibiotics, resistance to Extended-Spectrum Beta-Lactam antibiotics is a commonly occurring
phenomenon in the context of various infections including urinary tract
infections, respiratory tract infections, peritonitis and abdominal abscess. Extended-Spectrum
Beta-Lactamases (ESBLs) are the enzymes
capable of hydrolyzing penicillin and broad-spectrum cephalosporin and monobactams. This enzyme
is derived from TEM and SHV family.  Two
genes namely TEM and SHV genes are associated with ESBL producers mainly E. coli and Klebsiella
pneumoniae. TEM-1 and SHV-1 type
of beta-lactamase confers resistance to broad spectrum beta-lactam drugs which
is due to the specific mutation in structural gene. Other beta-lactamase gene includes
CTX-M, GES, OXA and PER-type.

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Understanding of
molecular mechanisms underlying the resistance and their pathological outcomes would
require both phenotypic as well as genotypic characterization of these enzymes.
In the context of Nepal, phenotypic characterization of ESBL producing strains
have been carried out extensively. However, knowledge of genotypic description
of these strains is poorly understood in the settings of Nepal.  In this project, we will study the prevalence
of TEM
and SHV genes,
associated with ESBL producing E. coli and Klebsiella pneumoniae
from various hospital samples.

 

Key words: Antibiotic
resistance, Extended spectrum beta-lactamases, TEM, SHV

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1.0  Background

 

Antibiotics are lifesaving miracle
drugs generally used in the treatment and stoppage of bacterial infections.
Global population today are totally dependent upon the antibiotics for minor to
major bacterial infections. However, extreme and
inconsistent use of these antibiotics has resulted in the rise of antibiotic
resistance, a scenario which is now posing a major public health problem
worldwide as it can easily cross international boundaries and spread between
the continents with ease in a great speed. The loss of efficacy of antibiotics against
the harmful pathogens has led to the increasing morbidity and mortality of
world population (Van Boeckel et al., 2014). And hence this condition warrants the quest for searching
novel therapeutics that would primarily require the knowledge of molecular
mechanisms underlying resistance (Zhang, Eggleston, Rotimi, & Zeckhauser, 2006).

 

Understanding
the present form of antibiotic resistance and
its genetic basis would provide the foundation to design and implement
stratagems to limit the advent and spread of resistance and progress innovative
therapeutics against these drug resistant organisms. Resistance is either
acquired or natural and is transferred via horizontal or vertical gene transfer
and also is due to gene expression alteration together with altered mechanism
of drug action (Alanis, 2005). There are
various factors that are proven or probable factors contributing to the
antibiotic resistance. Apart from errant use and over the counter availability
of antibiotics in the human medicine, excessive use of antibiotics and
chemicals in agriculture and livestock has led to emergence of drug-resistant
bacteria in the context of developing countries
. The current trend of globalization has added
the increased the vulnerability of countries to imported diseases, infectious
diseases and antibiotic resistance species. Natural environment acts as a
reservoir for antibiotic resistance genes and changes in the ecology may be one
of the important factor contributing to it (Martínez, 2008). Moreover, climate change and
antimicrobial resistance appears to be interconnected to each other, since
climate change and global warming could be responsible for the evolution of
newer and even severer resistance mechanisms within bacteria (Hawkey, 2015).

 

Multidrug
resistance is the phenomenon in which the bacteria acquires resistance to
multiple drugs. Resistance to multiple drug in bacteria is associated with the
presence of gene that codes for resistance to drug on R plasmids which is
achieved by transposons, integrons and ISCR elements. Other mechanism of
resistance includes multi drug efflux pump, alteration in mode of action of
drugs, mutational in alteration of target protein etc. (Nikaido, 2009). Despite advances
in antibiotic therapy, rapid emergence of
multidrug resistant strains remains unresolved. In this context, emergence of extended spectrum beta lactamase (ESBLs) producing
strains, methicillin resistant Staphylococcus aureus (MRSA),
vancomycin-resistant Enterococcus (VRE) and metallo-b-lactamase (MbL)-producing
Pseudomonas aeruginosa are
threatening concerns for disease management.

 

Among them, ESBLs
producer organisms are posing a serious threat to the world as they are showing
resistance towards most beta-lactam antibiotics including Penicillin,
Cephalosporins. E. coli and Klebsiella pneumonia are two
important bacteria which
contains the genes that codes for ESBLs being resistance towards beta-lactam
drugs (Paterson, 2006). E. coli is the
most recurrent cause of urinary tract infections, bloodstream infections,
intra-abdominal infections and leading causative agents of foodborne infections
worldwide. Similarly, Klebsiella pneumonia causes urinary and respiratory
tract infections and, in neonates it causes bloodstream infections (WHO Report, 2014). These ESBL producing
organisms confer
resistance to the beta-lactam antibiotics thus preventing the treatment.

 

Different
types of genes are associated with ESBLs which includes TEM, SHV, CTX-M, OXA,
PER, TLA, GES etc. TEM and SHV are plasmid encoded beta-lactamase genes grouped
as class A ESBLs. TEM and SHV type of ESBLs are not generally active against
cephamycins (cefotetan, cefoxitin, cefmetazole) or carbapenems (imipenem,
ertapenem, and meropenem). They can be repressed by beta-lactamase inhibitors
like clavulanate, sulbactam, or tazobactam (Paterson, 2006). TEM and SHV carrying bacteria are spreading
worldwide and are developing mechanism of resistance against beta-lactam
antibiotics. These plasmid mediated genes are derived from one or more amino
acid substitution in their active site (Jain & Mondal, 2008)Antibiotics
are a lifesaving agent which are used to target several against several pathogenic
bacteria. However, development of antibiotic resistance mechanisms by bacteria are
creating conditions where these, once life-saving drugs, no longer effectively
works out. Antibiotic resistance is the global upsetting trend and a
challenging problem for researchers from all fields worldwide. 

Among many
antibiotics, resistance to Extended-Spectrum Beta-Lactam antibiotics is a commonly occurring
phenomenon in the context of various infections including urinary tract
infections, respiratory tract infections, peritonitis and abdominal abscess. Extended-Spectrum
Beta-Lactamases (ESBLs) are the enzymes
capable of hydrolyzing penicillin and broad-spectrum cephalosporin and monobactams. This enzyme
is derived from TEM and SHV family.  Two
genes namely TEM and SHV genes are associated with ESBL producers mainly E. coli and Klebsiella
pneumoniae. TEM-1 and SHV-1 type
of beta-lactamase confers resistance to broad spectrum beta-lactam drugs which
is due to the specific mutation in structural gene. Other beta-lactamase gene includes
CTX-M, GES, OXA and PER-type.

 

Understanding of
molecular mechanisms underlying the resistance and their pathological outcomes would
require both phenotypic as well as genotypic characterization of these enzymes.
In the context of Nepal, phenotypic characterization of ESBL producing strains
have been carried out extensively. However, knowledge of genotypic description
of these strains is poorly understood in the settings of Nepal.  In this project, we will study the prevalence
of TEM
and SHV genes,
associated with ESBL producing E. coli and Klebsiella pneumoniae
from various hospital samples.

 

Key words: Antibiotic
resistance, Extended spectrum beta-lactamases, TEM, SHV

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1.0  Background

 

Antibiotics are lifesaving miracle
drugs generally used in the treatment and stoppage of bacterial infections.
Global population today are totally dependent upon the antibiotics for minor to
major bacterial infections. However, extreme and
inconsistent use of these antibiotics has resulted in the rise of antibiotic
resistance, a scenario which is now posing a major public health problem
worldwide as it can easily cross international boundaries and spread between
the continents with ease in a great speed. The loss of efficacy of antibiotics against
the harmful pathogens has led to the increasing morbidity and mortality of
world population (Van Boeckel et al., 2014). And hence this condition warrants the quest for searching
novel therapeutics that would primarily require the knowledge of molecular
mechanisms underlying resistance (Zhang, Eggleston, Rotimi, & Zeckhauser, 2006).

 

Understanding
the present form of antibiotic resistance and
its genetic basis would provide the foundation to design and implement
stratagems to limit the advent and spread of resistance and progress innovative
therapeutics against these drug resistant organisms. Resistance is either
acquired or natural and is transferred via horizontal or vertical gene transfer
and also is due to gene expression alteration together with altered mechanism
of drug action (Alanis, 2005). There are
various factors that are proven or probable factors contributing to the
antibiotic resistance. Apart from errant use and over the counter availability
of antibiotics in the human medicine, excessive use of antibiotics and
chemicals in agriculture and livestock has led to emergence of drug-resistant
bacteria in the context of developing countries
. The current trend of globalization has added
the increased the vulnerability of countries to imported diseases, infectious
diseases and antibiotic resistance species. Natural environment acts as a
reservoir for antibiotic resistance genes and changes in the ecology may be one
of the important factor contributing to it (Martínez, 2008). Moreover, climate change and
antimicrobial resistance appears to be interconnected to each other, since
climate change and global warming could be responsible for the evolution of
newer and even severer resistance mechanisms within bacteria (Hawkey, 2015).

 

Multidrug
resistance is the phenomenon in which the bacteria acquires resistance to
multiple drugs. Resistance to multiple drug in bacteria is associated with the
presence of gene that codes for resistance to drug on R plasmids which is
achieved by transposons, integrons and ISCR elements. Other mechanism of
resistance includes multi drug efflux pump, alteration in mode of action of
drugs, mutational in alteration of target protein etc. (Nikaido, 2009). Despite advances
in antibiotic therapy, rapid emergence of
multidrug resistant strains remains unresolved. In this context, emergence of extended spectrum beta lactamase (ESBLs) producing
strains, methicillin resistant Staphylococcus aureus (MRSA),
vancomycin-resistant Enterococcus (VRE) and metallo-b-lactamase (MbL)-producing
Pseudomonas aeruginosa are
threatening concerns for disease management.

 

Among them, ESBLs
producer organisms are posing a serious threat to the world as they are showing
resistance towards most beta-lactam antibiotics including Penicillin,
Cephalosporins. E. coli and Klebsiella pneumonia are two
important bacteria which
contains the genes that codes for ESBLs being resistance towards beta-lactam
drugs (Paterson, 2006). E. coli is the
most recurrent cause of urinary tract infections, bloodstream infections,
intra-abdominal infections and leading causative agents of foodborne infections
worldwide. Similarly, Klebsiella pneumonia causes urinary and respiratory
tract infections and, in neonates it causes bloodstream infections (WHO Report, 2014). These ESBL producing
organisms confer
resistance to the beta-lactam antibiotics thus preventing the treatment.

 

Different
types of genes are associated with ESBLs which includes TEM, SHV, CTX-M, OXA,
PER, TLA, GES etc. TEM and SHV are plasmid encoded beta-lactamase genes grouped
as class A ESBLs. TEM and SHV type of ESBLs are not generally active against
cephamycins (cefotetan, cefoxitin, cefmetazole) or carbapenems (imipenem,
ertapenem, and meropenem). They can be repressed by beta-lactamase inhibitors
like clavulanate, sulbactam, or tazobactam (Paterson, 2006). TEM and SHV carrying bacteria are spreading
worldwide and are developing mechanism of resistance against beta-lactam
antibiotics. These plasmid mediated genes are derived from one or more amino
acid substitution in their active site (Jain & Mondal, 2008)