Antibiotic Resistance and Extended

Spectrum Beta-Lactamases : Types,

Epidemiology and Treatment
Sibhghatulla Shaikh a, Jamale Fatima b, Shazi Shakil b,*, Syed Mohd. Danish Rizvi a, Mohammad Amjad Kamal c,d
a Department of Biosciences, Integral University, Lucknow 226026, India
b Department of Bio-engineering, Integral University, Lucknow 226026, India
c King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia d Enzymoic,
7 Peterlee Pl, Hebersham, NSW 2770, Australia
Received 24 February 2014; revised 9 August 2014; accepted 10 August 2014 Available online 17 August 2014

Ilham Revan Ananda, S.Ked | 1308012022

Journal Reading
dr. Alders A. K. Nitbani, Sp.B

SURGERY DEPARTMENT - RSUD PROF. DR. W.Z. JOHANNES KUPANG

FACULTY OF MEDICINE - NUSA CENDANA UNIVERSITY
2018
 Resistance of antibiotics has
become a worldwide problem.

INTRODUCTION The heightened use/ misuse of

antibiotics in human medicine,
agriculture and veterinary is
primarily contributing to the
phenomenon.
 Beta-lactam antimicrobial
agents exhibit the most
common treatment for
bacterial infections and
INTRODUCTION continue to be the prominent
cause of resistance to beta-
lactam antibiotics among
Gram-negative bacteria
worldwide.
 The persistent exposure of bacterial
strains to a multitude of beta-
lactams has induced dynamic and
continuous production and mutation
of beta-lactamases in these bacteria,
expanding their activity even against
INTRODUCTION
the newly developed beta-lactam
antibiotics.

These enzymes are known as

extended-spectrum b-lactamases
(ESBLs)
How does antibiotics work ?

5 major modes of antibiotic mechanisms

Interference with cell wall synthesis

Inhibition of protein synthesis

Interference with nucleic acid synthesis

Inhibition of a metabolic pathway

Disorganizing of the cell membrane

Antibiotic resistance mechanism

Antibiotic inactivation by
hydrolysis and redox process

Antibiotic inactivation by group

transfer

Antibiotic resistance via target

modification
Genetics of antibiotic resistance

Antibiotic inactivation by
hydrolysis and redox process

Antibiotic resistance via horizontal

gene transfer
ESBL definition and
classification
• There is no consensus of the precise definition of
ESBLs.
• ESBLs are a group of enzymes that break down
antibiotics belonging to the penicillin and
cephalosporin groups and render them ineffective.
• ESBL has generally been defined as transmissible beta-
lactamases that can be inhibited by clavulanic acid,
tazobactam or sulbactam, and which are encoded by
genes that can be exchanged between bacteria.
 Beta-lactamases are
commonly classified according
to two general schemes:

Bush–Jacoby–
Ambler molecular Medeiros
classification functional
classification
The Ambler scheme classifies b-lactamases into four
classes according to the protein homology of
enzymes. Beta-lactamases of :
class A, C, and D are serine b-lactamase and class B
enzymes are metallo-b-lactamases.

The Bush–Jacoby–Medeiros functional scheme is

based on functional properties of enzymes, i.e. the
substrate and inhibitor profiles.
 SHV type : sulfhydryl variable

TEM type : Temoneira

CTX type : Cefotaxime hydrolyzing capabilities

TYPE OXA type : oxacillin-hydrolyzing abilities

PER type :Pseudomonas extended resistant

GES type : Guiana extended-spectrum

VES-1 (Vietnam), BES-1 (Brazil), and other type

SHV type
• The SHV family of b-lactamases appears to be
derived from Klebsiella spp.
• Universally found in K. pneumoniae.
• incorporated into a plasmid which has spread to
other enterobacteria species.
• SHV-1 confers resistance to broad-spectrum
penicillins such as ampicillin, tigecycline and
piperacillin
• The SHV-1 b-lactamase is responsible for up to
20% of the plasmid-mediated ampicillin resistance
in K. pneumoniae species.
TEM type
• TEM-1, first reported from an E. coli isolate in 1965, has
substrate and inhibition profiles similar to those of SHV-1.
• TEM-1 is capable of hydrolyzing penicillins and first generation
cephalosporins but is unable to attack the oxyimino
cephalosporin.
• Klebsiella oxytoca, harboring a plasmid carrying a gene
encoding ceftazidime resistance, was first isolated in
Liverpool, England, in 1982. The responsible b-lactamase was
what is now called TEM-12. Interestingly, the strain came
from a neonatal unit which had been stricken by an
outbreak of K. oxytoca producing TEM-1. This is a good
example of the emergence of ESBLs as a response to the
selective pressure induced by extended-spectrum
cephalosporins.
CTX type
• A new family of b-lactamases that preferentially
hydrolyzes cefotaxime has arisen.
• In addition to the rapid hydrolysis of cefotaxime, another
unique feature of these enzymes is that they are better
inhibited by the b-lactamase inhibitor tazobactam than
by sulbactam and clavulanate
• CTX-M ESBLs were acquired by the horizontal gene
transfer from other bacteria using genetic apparatuses
such as conjugative plasmid or transposon.
Detection Phenotype detection

Genotype detection

Additionally, patients colonized or

infected with ESBL-producing
organism should be placed under
contact precautions to avoid
hospital transmission
 Phenotyping : use lab with a
susceptibility testing of the
microbes to the drugs that
given to the suspicious
specimen
Detection
Genotyping : using a gene
examination to determine
the type of ESBLs that the
patient has.
EPIDEMIOLOGY
• The epidemiology of ESBLs is quite
complicated.
• Additionally, there are various reservoirs,
including :
• the environment (e.g. soil and water),
• wild animals,
• farm animals, and
• pets.
• The final component entails transmission
from :
• food and water, and
• via direct or indirect contact (person to
person)
From an international aspect
SWEDEN
• The number of cases of ESBLs
increased by 100% from 2008 to
2011.
• According to data from the
European Antimicrobial
Resistance Surveillance System
(EARSS), 2.6% of E. coli and 1.7%
of K. pneumoniae strains in
Sweden were resistant to third-
generation cephalosporins in
2010.
EUROPE
• New TEM and the SHV enzymes
are still emerging in Europe.
• Number of subtypes still need so
much work on europe.
• The resistance exhibited by K.
pneumoniae has reached a
higher level with emergence of
carbapenemases such as OXA-
48, which was first found in
Turkey.
NIGERIA
• Another investigation was
conducted at a tertiary hospital
in Nigeria, among the overall
ESBL producing isolates, 35%
being community origin and
65% from hospitals.
AFRICA
• In Nigeria, ESBLs case counts
35% being community origin
and 65% from hospitals.
• Dramatic figures were also
obtained in a small study at an
orphanage in Mali, where 63%
of the adults and 100% of the
children were found to carry
ESBL-producing
Enterobacteriaceae that
showed extensive co-resistance
to other antibiotics.
AFRICA
• in Madagascar, Herindrainy et
al. (2011) observed that 10% of
non-hospitalized patients
carried ESBLs, in the majority of
the cases CTX-M-15, and these
investigators also found that
poverty was a significant risk
factor for carriage.
MIDDLE EAST
• The overall data on ESBL-
producing Enterobacteriaceae
in the countries of the Middle
East are extremely worrisome,
and this region might indeed be
one of the major epicenters of
the global ESBL pandemic.
ASIA
• The poor quality of drinking
water, in combination with a
lack of control over
prescription and sales of
antibiotics, are probably major
factors that have promoted the
development of resistance in
Asia
• Rapid increase in ESBL-
producing K. pneumoniae (up
to 60%) and E. coli (13–35%) in
different parts of China.
SOUTH AMERICA
• Highest prevalence of ESBL-
producing K. pneumoniae in the
world is seen primarily in Latin
America.
TREATMENTS
The Carbapenems
• (imipenem, meropenem, ertapenem,
doripenem) are still the first choice of
treatment for serious infections with
ESBL-producing E. coli and K.
pneumoniae.
• It has been reported that >98% of the
ESBL-producing E. coli, K. pneumoniae
and P. mirabilis are still susceptible to
these drugs.
The Fosfomycin
• There are some older drugs which can be used to treat
the ESBL-producing E. coli or K. pneumoniae infections.
Fosfomycin was reported of having admirable in vitro
activity against the ESBL-producing E. coli or K.
pneumoniae.
• Colistin is used in the treatment of multidrug resistant P.
aeruginosa, carbapenem resistant A. baumannii. Close
monitoring for the development of side effects can
improve the safety margin when prescribing the drug.
• Tigecycline is also one of the drugs in the pipeline which
can be considered for treatment.
• ESBLs bacteria has increased in recent years.
• The epidemiology of ESBL-producing bacteria
is becoming more complex.
• Probably, a ‘‘super bug’’, resistant to
relatively all licensed antibiotics, may rise in
the future. Constant and careful worldwide
surveillance for multidrug-resistant bacteria is
urgently warranted.
Antibiotic resistance and extended
spectrum beta-lactamases : Types,
epidemiology and treatment
Sibhghatulla Shaikh a, Jamale Fatima b, Shazi Shakil b,*, Syed Mohd. Danish Rizvi a, Mohammad Amjad Kamal c,d
a Department of Biosciences, Integral University, Lucknow 226026, India
b Department of Bio-engineering, Integral University, Lucknow 226026, India
c King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia d Enzymoic,
7 Peterlee Pl, Hebersham, NSW 2770, Australia
Received 24 February 2014; revised 9 August 2014; accepted 10 August 2014 Available online 17 August 2014

Ilham Revan Ananda, S.Ked | 1308012022

Journal Reading
dr. Alders A. K. Nitbani, Sp.B

SURGERY DEPARTMENT - RSUD PROF. DR. W.Z. JOHANNES KUPANG

FACULTY OF MEDICINE - NUSA CENDANA UNIVERSITY
2018