Virulence Factors of Klebsiella pneumoniae Isolates from Iraqi Patients

Abstract

The aim objective of this research is a review study of the virulence factors of Klebsiella pneumoniae isolated from Iraqi patients, where

Full text

Sys Rev Pharm 2020; 11(6): 916 921
A multifaceted review journal in the field of pharmacy
E-ISSN 0976-2779 P-ISSN 0975-8453
916 Systematic Review Pharmacy Vol 11, Issue 6, 2020
Virulence Factors of
Klebsiella pneumoniae
Isolates
from Iraqi Patients
Saade Abdalkareem Jasim
1
, Sumaya Ayad Abdulrazzaq
1
, Sarah ibrahim hashoosh
2
, Raed Obaid Saleh
1
1Medical laboratory techniques department, Al-maarif University College, Iraq
2Medical laboratory techniques department, Ashur University College, Iraq
Corresponding author:
Saade Abdalkareem Jasim
E-mail: saade1988@auc-edu.org
Article History: Submitted: 22.04.2020 Revised: 20.05.2020 Accepted: 28.06.2020
ABSTRACT
The aim objective of this research is a review study of the virulence
factors of
Klebsiella pneumoniae
isolated from Iraqi patients, where
the world is currently facing a major problem orwe say a war between
bacteria and antibiotics. The most important of these bacteria is
K.
pneumoniae
and it is one of the opportunistic bacteria and is
considered one of the causes of nosocomial infection, contamination
of wounds , Urinary tract infection and contamnation of operating
theaters. Where these bacteria are distinguished by their resistance to
β-lactam antibiotics to produce β-lactamase as well as having a
lipopolysaccharide and an important virulence factor is the capsule that
resists phagocytosis. An important factor for these bacteria is their
formation of biofilm, which is primarily responsible for chronic
infections because of their resistance to phagocytosis and killing due
to humoral and cellular immunity. The excessive use of antibiotics,
which led to the resistance of bacteria to these antibiotics and is the
main caus e of the current problems of the world, as microorganisms
have the ability to develop mechanisms that enable them to overcome
these antibiotics more quickly and difficult to find alternatives to these
antibiotics. Most of the changes that make bacteria resistant to ma ny
antibiotics are acquired changes that are caused by genetic changes or
acquisition of resistant genes that make them resistant to many
antibiotics.
Keywords
K.pneumoniae
, vieulence factors, β-lactamase,
Lipopolysaccharid, Capsule.
Correspondence:
Saade Abdalkareem Jasim
Medical Laboratory Techniques Department, Al – Maarif University
College, Iraq
E-mail: saade1988@auc-edu.org
DOI: 10.31838/srp.2020.6.129
@Advanced Scientific Research. All rights reserved
INTRODUCTION
We will focus on the virulence factors of isolated samples
from Iraqi patients to see how the K. Pneumoniae have
developed resistance to antibiotics. The excessive use of
antibiotics and the resistance of bacteria in general,
especially the K. pneumoniae, to many of these antibiotics,
despite the development taking place in the antibiotics, led
to great risks in obtaining alternatives to these antibiotics
due to the development of resistance in the bacteria to
inhibit the action of these antibiotics and increase their
virulence [1]. K. pneumoniae is considered one of the
important cause pathogen from nosocomial infection
especially for a patient who suffers from
Immunocompromised or who are taking drugs
immunosuppressed and who suffer from increase iron
concentration in blood [2].
Virulence factors
K. pneumoniae possess a number of virulence factors which
share with pathogen and include capsule antigens, adhesion
factors, enterotoxin produce like lipopolysaccharide as well
as resistance killer effect for serum and system the gain on
iron (Siderophore) and multi resistance for antibiotics
which considered the main reason in spread acquired
infections in hospitals, as the percentage infections 80%
which led to find alternative treatments and we will mention
some Iraqi research on these factors:
The capsule
The capsule is considered fundamental to the virulence of
Klebsiella, as it protects the bacterium from phagocytosis
and prevents the bacteria by bactericidal serum factors [3].
Some serotypes or capsular types of K. pneumoniae, e.g. (K1,
K2, K5, K54 and K57), have been correlating with invasive
human infection illness. K1 was found among isolates
causing Friedlӓnders pneumonia, and has more recently
been associated with pyogenic liver abscesses [4].
[5] studied the association between K-type, sequence type
(ST) and virulence gene content. The authors concluded
that K-types are not associated with specific K. pneumoniae
clones and that K-types are published among unrelated
clones by horizontal transmit of the cps operon, which
encodes the synthesis of capsular polysaccharides. During
recent years, several genes encoding virulence factors K.
pneumoniae have been described: the plasmid-borne rmpA
regulates the mucoid phenotype [6], wcaG is associated with
reinforced bacterial get-away from phagocytosis [7], kfu is
involved in iron acquirement, fimH encodes type 1 fimbriae,
mrkD encodes type 3fimbriae and cf29A encodes the non-
fimbrial adhesion factor CF29K [5].
In a study conducted by [8], the genotype K1 and K2 were
used. Of the 46 isolate from these bacteria, eight were
positive for K1, fourteen positive for K2 and 3 positives for
both, while eighteen isolate did not contain either K1 or K2.
In another study conducted by [9], forty isolates showed
twenty three isolate carrying the K1 genotype, while eleven
positive isolate of the K2 genotype and six isolates did not
carry either type.
Other study by [10], one hundred sample of urine and
sputum were collected from patients at Al-Yarmouk
Teaching Hospital in Baghdad. 38 sample were obtained
from Klebsiella pneumoniae and were only from UTI. These
isolates showed resistance to most of the antibiotics such as
Ceftazidime Augmentine, Ceftriaxone , and Cefotaxime ,
while lower resistance was shown to both Imipenem and
Meropenem. The results also showed only four samples that
were positive for the wzy gene, represented by K19 and K20,
K21, K22.
Thirty nine isolate of K. pneumoniae were diagnosed in Al-
Diwaniya Teaching Hospital for various cases (sputum,

Saade Abdulkareem Jasim et al / Virulence Factors of Klebsiella pneumoniae Isolates from Iraqi Patients
917 Systematic Review Pharmacy Vol 11, Issue 6, 2020
urine, burns and wounds). The presence of capsule antigen
(K) was detected by Multiplex PCR technique. The results
showed that there were three serotypes K1, K57 and K2 that
were more present than other types [11].
In another study by [12] of seven isolates of K.pneumoniae
out of 34 sample. Thirty four samples were collected from
Ramadi Teaching Hospital and Burns Specialized Hospital
in baghdad, where the results showed that the isolates were
resistant to most antibiotics as these seven isolates were
diagnosed through a PCR to detect the mag A gene for
serotype K1 and also for rcsA gene for genotype K2, the
results showed that 5 isolates were related to type K2 and the
remaining two isolates did not have any of the two types.
Lipopolysaccharide
Lipopolysaccharide represents an important and essential
factor in bacterial pathogenicity, especially K. pneumoniae,
as it is one of the superficial compositions of bacteria that
help it to resist phagocytosis, and it is characterized by its
ability to activate the complement factor [3]. It participates
in protecting bacteria against the host's Complement
System. LPS consists of three parts: Lipid A, Core
polysaccharide, and O antigen, which consists of a side
chain of the polysaccharide, and the antigen O is responsible
for the bacteria's resistance to killing [13]. K. pneumoniae
have eight serotypes, and serotype O1 and O2 are the most
common.
K. pneumoniae O-antigen-deficient strains, community
acquired pneumonia (CPS) protects the micro-organism
against complement killing [14]. K. pneumoniae serotype
O1:K1 plays a study role in virulence by transfer resistance
to serum killing and by promoting bacterial dissemination
to and colonization of internal organs after the start of
bacteraemia [15].
In a study conducted by [16] where the CPS genotype was
used, among 46 isolate of these bacteria, 43 were positive for
this gene while only 3 isolates were missing for this gene.
Two types of core polysaccharide (Type I and Type II) have
been diagnosed produced by these bacteria, which are
synthesized by two different groups of wa gene cluster. [17].
Outer membrane proteins
Is one of the important proteins of the gram negative
bacteria are present in the outer membrane OmpA, which is
characterized by most of the Enterobacteracea. OmpA is
independent of the core polysaccharide in K. pneumoniae ,
which has an important role in preventing the activation of
epithelial cells in the airway as it acts on NF-kB-p38- and
p44 / 42- dependent pathways and thus particibate to the
attenuation these cells through the inflammatory response
[18].
An important factor that is produced by the Klebsiella
pneumoniae is the expression of efflux pump AcrAB, whose
action is not limited to exporting antibiotics only such as
- lactams), but also works to export anti-
microbial agents derived from the host. The loss of AcrAB
leads to a loss of the ability to cause pneumonia [19].
In a study by [20], on the resistance of multiple drugs by K.
pneumoniae, which has the wide resistance to many
antibiotics in Iraqi hospitals, Efflux pumps AcrAB was
studied where 100 samples were taken from various sources
from the medicine city and diagnosed by the 16S-23S
rDNA gene It is present that 60 isolate were for K.
pneumoniae, after which efflux pump AcrA gene was
detected using a specific primer and it appeared that there
are 26 isolates producing this gene. The results showed by
studying the gene expression AcrAB-Tolc efflux pump using
q(RT-PCR) that there is a relationship between the gene
expression and chloramphenicol concentration, as well as
the gene expression of the same gene increases from
exposure to the Imipenem with some differences, while
there was a decrease in the expression of Amikacin and
Ciprofloxacin.
In a study in which the researcher collected 195 different
clinical samples from three hospitals in the city of Al-Najaf
and 50 samples from the hospital environment, where the K.
pneumoniae was diagnosed by biochemical and cultural
tests and the results showed that 89 isolates were for the K.
pneumoniae where the resistance to quinolone antibiotics
was examined by their growing on the MacConkey agar
medium supported with the ciprofloxacin, it showed that 34
isolates were resistant to the ciprofloxacin antibiotic. As for
the sensitivity test for 18 antibiotics, the results showed that
34 isolates had the characteristic of Multidrug resistant
(MDR). Also in this study, the presence of resistance genes
(aac (6 ') -Ib-cr, qepA, qnrS and qnrB) was detected, where
the plasmid resistance gene showed aac (6') -Ib-cr gene is
common among of other genes where it was found in 14
isolation alone or appeared with the qnrS gene, also at 8.82%
for three genes aac (6 ') -Ib-cr, qepA, qnrS and showed
2.94% of isolates two genes are aac (6') -Ib-cr and qnrS while
the qnrB gene appeared in only one isolate was sourced
from wounds [21].
Hypermucoviscous phenotype
A distinguishing factor of hvKP strains is its
hypermucoviscous phenotype. The great majority, but not
all of the strains cause community-acquired pyogenic liver
abscesses (CA-PLA) possess this phenotype [6].
In a study conducted by [16] where the mag viscosity gene
was investigated for 46 isolates of these bacteria, it gave 21
positive isolates. and the genes responsible for regulating
viscosity and mucous matter were studied using three types
of genetic indicators (rmpA1, rmpA rmpA2). Results showed
that 21 isolates contained the rmpA gene, while only 19
isolates gave a positive result for these indicators rmpA1 and
rmpA2.
In another study, forty isolates of K. pneumoniae were used,
where the results showed that eleven strains were carriers of
the rmpA gene, where five strains were carrying type K1 and
also five strains of type K2 and only one strain of the two
serotype together. The results also showed that the positive
strains of the serotype K1 serotype gave amplification of
both magA, rmpA and 16S rRNA genes while the K.
pneumoniae strains of type K2 and non-carrier of the rmpA
gene gave only amplification of serotype K2 and 16S rRNA
and also the strains carrying type K1 and non-carrier of the
gene were magA and 16S rRNA and finally the non-carrier

Saade Abdulkareem Jasim et al / Virulence Factors of Klebsiella pneumoniae Isolates from Iraqi Patients
918 Systematic Review Pharmacy Vol 11, Issue 6, 2020
strains of the two types K1 as well as the K2 and non-carrier
of the rmpA gene gave a positive result for the 16S rRNA
gene. Through the results above, the results show that the
genotype magA and k2A as well as any possible that is useful
in detecting serotype K1 and K2 for K. pneumoniae [9].
Siderophores and Fimbrial adhesins
Sixty-one isolates of K. pneumoniae were isolated and
diagnosed from 433 samples of children suffering from
diarrhea in Kirkuk Hospitals, where virulence factors were
determined for these bacteria and the results showed that all
K. pneumoniae isolates were produced for the capsule,
urease and siderophore. The results also showed that all
isolates have the ability to adhere to human buccal cavity
epithelial cells [22].
In a study in which K. pneumoniae were found to be able to
remain in the urinary tract and their relationship to the
genes responsible for forming the biological membranes
fimA, fimH, mrkA and mrkD, the study included 50 isolated
K. pneumoniae isolates from patients with UTI and these
isolates were diagnosed by the VITEK 2 system apparatus or
their ability to produce biofilms by using tissue culture
plate method. Female infections were more than males
50/44 and 6/44 respectively, and results also showed that
about 72% of isolates were biofilm production. Using the
PCR technique, 12 isolates were detected, all carrying the
fimA, fimH, mrkA and mrkD genes [23].
Virulence factors were detected for 32 isolates of K.
pneumoniae isolated from various cases (sputum, urine,
burns and blood) in Al-Najaf Governorate. As the capsule,
hypermucoviscosity, and ability to form biofilms , produce
siderophores and as well as the production of -lactamase
were revealed. PCR was used to detect genes that encode
these factors (fimH, ycfM), (kfu: iron uptake system, entB:
enterobactin, irp-2: yersiniabactin), capsule synthesis or
invasions (rmpA, uge, wabG) and -lactamase (SHV, TEM).
The results showed that 100% of the isolates produced the
capsule, biofilms and the siderophores, while for the
hypermucoviscosity only 62.5% of the isolates had the
ability to produce this factor. Also, most virulence genes
appeared as fimH-1, ycfM and entB (100%), uge and TEM
(93.75%), wabG and SHV (87.5%). While the Kfu and rpmA
genes appeared 65.62 and 62.5%, respectively. The lowest
percentage was for the Irp-2 gene (37.5%). As for its ability
to produce -lactamase, 62% of the K.pneumoniae isolates
showed their ability to produce this enzyme [24].
Lactam antibiotics
Due to their diversity, broad spectrum of activity and low
- lactams are the most prescribed antibiotics
-lactam ring in common. Due to differences
-lactams may be classified into the
following main groups: penicillins, cephalosporins,
monobactams and carbapenems [25]. -lactams target the
bacterial cell wall synthesis and act by binding covalently to
penicillin binding proteins (PBPs).
Carbapenem- -lactamases (Carbapenemases)
Carbapenemases are clinically important because they
destroy and so may confer resistance to carbapenems (and
-lactams). K. pneumoniae that produce
class A Carbapenemases (KPC) are frequently identified
worldwide [26]. K. pneumoniae Carbapenemases (KPCs) It
is considered one of the important enzymes that work to
-lactam antibiotics, as it works to break down the
-lactam ring and inhibit the action of these antibiotics,
especially class A.
The researcher [27] collected 42 isolates of K.pneumoniae
from burn infections in Baghdad hospitals, where sensitivity
test was tested for all isolates for a number of antibiotics and
the results showed that the ratios appeared as doxycycline
(100%), tetracycline (95.23%), cefotaxime and piperacillin (
85.71%), ceftriaxone (88.09%), trimethoprim-
sulfamethoxazol (83.71), ticarcillin (78.57), aztreonam
(71.2%) ceftazidime (69.4%) ciprofloxacin ( 59.52%) ,
gentamycin (26.16% ) , imipenem (21.42% ) and finally
amikacin and meropenem (19.04 %).
In a study conducted by the researcher [28] to detect the
presence of blaOXA-23 gene between 117 isolate of K.
pneumoiae obtained from the hospitals in Al-Hilla, where
the results showed that the highest percentage was found in
stool followed by sputum samples. The initial sensitivity test
of -lactam antibiotics showed that 91 isolates were resistant
to ampicillin and amoxicillin. About 17 isolates showed
their resistance to carbapenems antibiotics, and the presence
of blaOXA-23 gene was detected in these isolates using PCR
technique, the results showed that 15 isolates of K.
pneumoniae were carrier of this gene.
In another study, 135 urine samples were collected from
patients with cystitis and confirmed by clinical diagnosis at
Al-Hilla Teaching Hospital. The samples were diagnosed by
biochemical and VITEK2 system tests. The results showed
that 23 isolates were K. pneumoniae (31.9%) of the total
samples. All of these isolates were tested for sensitivity to
antibiotics, and the isolates showed high sensitivity to the
amikacin 2(8.7%) norfloxacin 7(30.4%) and tobramycin
9(39.1%), while it showed resistance to the antibiotics
ampicillin 23(100%), ceftazidim 20(91.3%), cefotaxime
19(82.6%) and cefepime 17(73.9%) and ertapenem
10(43.5%). The researcher used DDST as well as chromatic
ESBL medium, MIC test strip and chromatic CRE medium
for KPC for investigation of ESBL and KPC [29].
The (blaKPC1 and blaKPC2) genes were detected for a number
of Iraqi samples isolated from different hospitals for patients
with wounds, burns, sputum and urine in 2015 using
specific primers of the first gene blaKPC1 and the second gene
blaKPC2 where most of the samples showed their resistance
to the carbapenem antibiotics and production of
Carbapenemases, there are a number of variations showed
compared to NCBI [30,31].
In another study conducted by [32], there was a variation in
the resistance of carbapenem antibiotic, Among the 53
isolates of Klebsiella pneumoniae most isolates were
sensitive to Meropenem and Imipenem antibiotic 90.5% and
77% respectively. The isolates showed higher resistance to
third generation cephalosporins. Carbapenemases
production was detected by the modified Hodge test, five
carbapenem resistant K. pneumoniae isolates (K2, K3, K4,

Saade Abdulkareem Jasim et al / Virulence Factors of Klebsiella pneumoniae Isolates from Iraqi Patients
919 Systematic Review Pharmacy Vol 11, Issue 6, 2020
K34 and K35) gave positive results for this test out of a total
of 53 isolates. In the other part in this study, detection of
blaKPC gene by PCR technique was carried out on all fifty-
three K. pneumonia isolates. Even though five isolates gave
positive modified Hodge test, only one isolate (K2) gave
specific identification for blaKPC gene.
Another study, the results showed that 27 isolates of K.
pneumoniae bacteria in Al-Hilla Teaching Hospital for
isolated samples of urine and wound infection, that there is
resistance to tetracycline and ceftriaxoneh antibiotics, and
showed sensitivity to amikacin as well as imipenem [33].
In a study that collected 61 urine and stool samples in Al-
Diwaniyah governorate to detect encoded genes for -
lactamase from patients with bladder and colon cancer.
Where the results showed that E. coli and K. pneumoniae in
urine samples 17 out of 23 samples, while the stool samples
were 19 out of 26 samples and the samples were resistant to
three classes of antibiotics. The PCR technique was used to
detect the blaTEM and blaSHV genes, where it was found that
most isolates carried at least one of the genes, and the
highest was the blaSHV gene, then blaTEM at a rate of (66.7%)
and (55.6%), respectively [34].
In a study conducted by [35] eighty isolates of K.
pneumoniae among elderly patients (smokers and non-
smokers) with chronic pneumonia in Al-Najaf Hospital.
The results showed the sensitivity of a number of antibiotics
that there was a variation in the levels of resistance between
the antibiotics (amoxicillin, nitrofurantoin, Amoxiclav,
Cefotaxime, Ceftriaxone, Ceftazidime, Gentamicin,
Amikacin , Tobramycin and Tetracycline), and it was also
found through the results that all the isolates of K.
pneumoniae from smoking patients were resistant to all
antibiotics compared to non-smokers. The results revealed
that through detection of genotypic, 45 were carriers of the
blaTEM gene, 31 were carriers of the blaSHV gene, while 18
isolates were carriers of both genes.
Due of the necessity of detection resistance genes, the
researchers [36] collected eighty seven isolated urine
samples from Al-Hilla Teaching Hospital for patients
suffering from UTI, 34 isolate were gram negative bacilli ,
including 14 isolates that were for K. pneumoniae was
produced for carbapenemase. The genotype was detected by
the PCR of the bla-IMP and bla OXA-48 genes, where results
showed that 5 (35.7%) and 3 (21.4%) of K. pneumoniae were
positive for blaIMP genes and blaOXA-48 genes respectively .
Histamine- producing bacteria (HPB)
In a study by [37], fifty one specimen were collected from
patients with respiratory infections in the Basra city . K.
pneumonia was diagnosed by morphology and biochemical
characteristics, as well as colonies culture on the Niven's
agar media as the colonies of purple color are an indicator of
bacteria producing histamine. All samples of K. pneumonia
are diagnosed by the HDC gene and its expression is
detected. The results showed that only 11 strains of
Klebsiella pneumonia were positive for the production of
histamine and most of them were sensitive to Trimethoprim
but are resistant to Ampicilin, Sulbactam / Ambicillin.
In a diagnostic study by the researcher [38] for a number of
isolated samples from different clinical sources (Sputum,
wounds smear and Urine) through the 16Sr RNA gene, the
results showed that among the 25 isolates 10 samples from
the K. pneumoniae showed this evidence of the
pathogenicity of these bacteria and their resistance to
antibiotics.
CONCLUSION
Through a review of many research studies of the Iraqi
isolates of K. pneumoniae within 5 years a go, it became
apparent that over time, the ability of these bacteria to resist
antibiotics increases through the development of the
virulence factors they possess or possess by acquiring new
characteristic. This indicator shows the difficulty of
discovering new antibiotics that work to kill these bacteria
therefore, plant extracts have been used recently to inhibit
them.
ACKNOWLEDGEMENTS
Thank fullest to the Al-maarif University College for its
continuous support to researchers, as well as thanful to Iraqi
researchers who contributed to enriching this research.
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