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Pattern of clinical drug resistance and occurrence of Gram negative bacterial

neonatal sepsis at a tertiary care hospital

Article in Pakistan Journal of Pharmaceutical Sciences · September 2021

DOI: 10.36721/[Link].1873-1878.1

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 [Link]/10.36721/[Link].1873-1878.1

Pattern of clinical drug resistance and occurrence of Gram negative

bacterial neonatal sepsis at a tertiary care hospital

Aqsa Ahmad1, Noreen Sarwar2, Rizwan Aslam1, Sultan Ali1, Bilal Aslam3,
Muhammad Adnan Arshad4, Hira Hameed1 and Muhammad Imran Arshad1*
1
Institute of Microbiology, University of Agriculture, Faisalabad, Pakistan
2
Department of Microbiology, University of Veterinary & Animal Sciences, Lahore Pakistan
3
Department of Microbiology, Government College University, Faisalabad, Pakistan
4
Department of Paediatric Medicine, Allied Hospital, Faisalabad Medical University, Faisalabad, Pakistan

Abstract: Sepsis is a leading cause of neonatal deaths across the world. Gram-negative rods such as Klebsiella and E.
coli are major cause of sepsis in neonates. With a mortality rate of 1-4 deaths per thousand live births, sepsis is the
second most important cause of neonatal deaths in the developing countries. The present study was designed to
determine the occurrence of Gram-negative bacteria in neonatal sepsis and to find antibiotic susceptibility of isolated
microbes. Blood samples of 100 neonates (1-89 days old) were sub cultured on MacConkey’s and Blood agar for
isolation of Gram-negative bacteria. A total of four bacterial species were isolated including Klebsiella (35.71%), E. coli
(28.57%), Acinetobacter (21.42%) and Proteus (14.28%). Gram-negative bacteria were isolated more commonly from
EOS (early onset sepsis) as compared to LOS (late onset sepsis). Klebsiella isolates from neonates showed sensitivity to
imipenem (70%) followed by ceftazidime (40%) and cefotaxime (40%) and high resistance was shown by
sulfamethoxazole (80%) and amikacin (70%). E. coli associated with neonatal sepsis were sensitive to imipenem (63%)
while highly resistant to cefotaxime (75%) and ciprofloxacin (62%). For Acinetobacter high sensitivity was found for
ceftazidime (50%) and resistance was shown to ciprofloxacin and sulfamethoxazole (100%). Proteus showed high
sensitivity to amikacin (75%) and high resistance to imipenem and ciprofloxacin (75%). In conclusion, Gram-negative
associated neonatal sepsis was found in the studied subjects and drug resistance was observed to clinically used
antibiotics.

Keywords: Drug resistance, neonatal sepsis, frequency, bacterial infection.

INTRODUCTION Salmonella spp and Haemophilus influenzae (Yadav et

al., 2018). EOS is considered to be vertically transferred
Sepsis is characterized by signs and symptoms that is from mother and E. coli is the leading cause among
associated with bacterial, viral and fungal infections and Gram-negative organisms, while LOS is considered to be
colonization of these microbes in the host. Neonatal transmitted horizontally or vertically. E. coli and other
sepsis is a leading cause of death all over the world, Gram negative organisms along with coagulase-
mainly in developing countries (Thapa and Sapkota, negative Staphylococci (CoNS), Staphylococcus aureus
2019) and it is categorized as early onset sepsis (EOS) i.e. and Candida albicans are responsible for sepsis
beginning of symptoms within 72 hours of birth and late (Akbarian-Rad et al., 2020).
onset sepsis (LOS) in which symptoms appeared after 72
hours of birth (Chaurasia et al., 2019). In 50% of sepsis Lymphocytes and neutrophils are the most important
cases, lethality is due to hospital acquired sepsis. It is elements of immune system which fight with the
more severe form of sepsis and it showed more resistance pathogens at initial stage. In case of sepsis a strong
to antibiotics as compared to type of sepsis present upon adhesion is formed between the endothelium and
admission (Meyer et al., 2018). Risk factors responsible neutrophil causing failure in migration of neutrophil to
of causing neonatal sepsis include premature birth, low site of infection. Release of cytokines and bacterial
birth weight and perinatal asphyxia. More factors like products in sepsis are involved in delay of neutrophil
umbilical cord care practice, prenatal care, delivery type apoptosis resulting in increase of sepsis severity (Wilar,
and settings are also considered the cause of neonatal 2019).
sepsis (Thapa and Sapkota, 2019). Pathogens involved in
neonatal sepsis differ all over the world. Gram negative Diagnostic tests for neonatal sepsis involve inflammatory
organisms are more commonly reported in developing biomarkers (procalcitonin test, C- reactive protein) and
countries (Mohsen et al., 2017). Gram negative organisms complete blood count. The most commonly used method
involved in sepsis are Escherichia coli, Pseudomonas spp, for diagnosis in neonatal intensive care unit is by blood
Neisseria meningitides, Klebsiella spp, Enterobacter spp, culture also called as rule out sepsis. This method is used
as a reference standard for diagnosis of neonatal sepsis
*Corresponding author: e-mail: drimranarshad@[Link] (Durrani et al., 2019).
Pak. J. Pharm. Sci., Vol.34, No.5(Suppl), September 2021, pp.1873-1878 1873
Pattern of clinical drug resistance and occurrence of Gram negative bacterial neonatal sepsis at a tertiary care hospital

The intense increase of antimicrobial resistance in samples were transferred to the Institute of Microbiology
pathogens is a worldwide concern of this era which needs for further processing.
urgent strategies at national and international level. The
cases of infections due to multidrug resistant bacteria Phenotypic examination of neonatal blood samples
(MDR) are increasing day by day both in developing and The broth containing blood samples were incubated at
highly developed countries (Folgori and Bielicki, 2019). 37 ̊C for 7 days and observed daily to check the turbidity.
The first line antibiotic for neonatal sepsis has been Each sample was sub cultured on 3rd, 5th and 7th day on
penicillin along with aminoglycoside but there is MacConkey’s agar and Eosin Methylene Blue agar
unrestrained resistance in public for these antibiotics. For (Oxoid Ltd.) for isolation of Gram-negative bacteria.
second line drugs; carbapenems and third- generation Gram negative bacteria were further purified on above
cephalosporins are used but due to spread of ESBL mentioned agars (fig. 1). Bacterial colonies were
enzyme, E. coli, Acinetobacter and Klebsiella became characterized on the basis of morphology, Gram’s
resistant to these drugs (Sands et al., 2021). Currently staining and biochemical tests which include catalase test,
there is no vaccine available for the control of neonatal coagulase test, citrate utilization test, triple sugar iron agar
sepsis in developing countries or low-to-middle-income test, indole test, methyl red test, oxidase test and urease
countries (LMICs). However, choosing broad spectrum test. Blood cultures that do not show any growth after sub
antibiotics as 1st line treatment against these resistant culturing were considered negative. However, samples
organisms is better option as compared to second line that show growth on 3rd and 5th day were considered
empiric antibiotics along with preventative strategies. The positive for sepsis.
present study aimed to determine the occurrence of
Antibiotic susceptibility testing
neonatal sepsis and antimicrobial susceptibility pattern of
Antibiotic susceptibility testing for Gram negative
Gram negative associated neonatal sepsis.
bacteria was performed by Kirby Bauer disc diffusion
MATERIALS AND METHODS method. Antibiotic discs (Oxoid, UK) including
imipenem 10µg, amikacin 30µg, ciprofloxacin 5µg,
The study was carried out in accordance with Institutional ceftazidime 30µg, sulfamethoxazole 30µg and cefotaxime
Bioethics Committee (IBC) of the University of 30µg were applied. Zones of inhibition of different
Agriculture Faisalabad and Allied Hospital Faisalabad, antibiotic discs were measured and interpreted as
Pakistan (No., 13409-12, dated as 02-04-2019). The resistant, susceptible an intermediate according to CLSI
neonatal blood samples were collected after taking an 2017 criteria.
informed consent from the parents of the neonates with
full compliance. STATISTICAL ANALYSIS
The data of neonatal sepsis and association of risk factor
Sample collection from neonates was analyzed by Graphpad Prism version 5 using chi
A total of 100 blood samples were collected aseptically square test and P value < 0.05 was considered to be
from neonatal sepsis cases from pediatric ward of tertiary statistically significant.
care Allied Hospital Faisalabad. The inclusion criteria
were the neonates both males and females with age RESULTS
ranging from 0-89 days. Blood samples were collected
before the beginning of antimicrobial therapy (Li et al., Frequency of Gram-negative bacteria in blood samples
2019) with the help of trained paramedical staff by using of neonates
aseptic techniques (Dalal et al., 2017). One ml of blood Out of 100 blood samples 28 were confirmed for
samples from neonates were taken in 9ml of Brain Heart microbial growth and 72 samples showed no growth on
Infusion Broth (Oxoid Ltd) having ratio 1:10. Blood culture media. Out of 28 positive blood samples, 10

Fig. 1: Representative agar colony morphology of Gram-negative isolates from neonatal sepsis on specific media (A)
Klebsiella (B) Acinetobacter (C) Proteus (D) E. coli.
1874 Pak. J. Pharm. Sci., Vol.34, No.5(Suppl), September 2021, pp.1873-1878
 Aqsa Ahmad et al

isolates were identified as Klebsiella (10%), along with E. susceptibility pattern of Gram-negative bacteria in
coli (8%), Acinetobacter (6%) and Proteus (4%) as shown neonates in a tertiary care hospital in Pakistan.
in fig.1.
Gram negative bacteria were isolated from 28% of
Frequency of Gram-negative bacteria with respect to the neonatal blood samples. A study conducted in Kolkata,
age of neonates India reported (42.94%) cases of Gram negative bacilli
The frequency of Klebsiella (10%) and E. coli (8%) were much higher than that reported in present study (Dutta et
found high in neonates of age 1 to 4 days. Acinetobacter al., 2020). The rate of isolated Gram negative bacteria
showed high positivity (6%) in neonates of age 5-8 days from neonatal sepsis had been reported high (69.6%) in
followed by Proteus (4%) from age 5 to 12 days. The Nepal (Thapa and Sapkota, 2019).
significant frequency of Gram-negative bacteria was
found in blood samples of neonates as shown by chi Neonatal sepsis is categorized as EOS and LOS and we
square test (P =.005) (table 1). found that Gram negative bacteria were more common in
EOS (60%) as compared to LOS (40%). A study
Frequency of EOS and LOS in neonates with respect to conducted in Nigeria reported incidence of Gram negative
age and gender bacteria in EOS as (77.2%) (Sa’adu et al., 2019). Study
The frequency of EOS was found to be (60%) as conducted in Nepal reported high cases of EOS (78.3%)
compared to LOS (40%). Neonates of 5-8 days old (Pokhrel et al., 2018). However, study in Switzerland
showed high prevalence and significant results (P=.020) reported prevalence of Gram-negative bacteria in EOS as
in EOS (37%) and (19%) in LOS (table 2). The (20%) lower than that recorded in present study. This
significant presence (P=.027) of EOS and LOS were high might be related with variation in area, hygienic
in female (55%) as compared to male neonates (45%) as conditions and use of antibiotics (Giannoni et al., 2018).
shown in table 3.
In sepsis multi drug resistant organisms are crucially
Antibiotic susceptibility pattern of Gram-negative involved in causing high mortality as compared to non-
bacteria isolated from neonatal sepsis multi drug resistant bacteria (Yusef et al., 2018). A study
The antibiotic susceptibility pattern of Klebsiella isolates in India showed that use of broad-spectrum antibiotics
showed highest susceptibility (70%) to imipenem leads to high resistance in K. pneumoniae.
followed by (40%) susceptibility to ceftazidime and Aminoglycosides, carbapenem, 3rd generation
cefotaxime as shown in table 4. The Klebsiella isolates cephalosporins, fluoroquinolones along with other drugs
(n=2) showed intermediate susceptibility (30%) to showed susceptibility against K. pneumoniae (Patidar and
ciprofloxacin and cefotaxime (40%). Antibiotic Patidar, 2020). We found high sensitivity (70%) against
susceptibility pattern of E. coli isolates from neonates imipenem and resistance (70%) against amikacin, which
showed high susceptibility (63%) to imipenem and was reported in previous study (Marando et al., 2018).
sulfamethoxazole followed by (50%) susceptibility to Study from Ghana reported that Enterobacteriacea
amikacin as shown in table 4. E. coli isolates showed showed 100% resistance to cefotaxime, 50% to
intermediate susceptibility to ceftazidime and cefotaxime ceftriaxone and 50% to gentamicin. However Proteus
(25%). Neonatal sepsis associated Acinetobacter was mirabilis did not show resistance to cefotaxime in a
found to be sensitive to ceftazidime (50%), imipenem and previous study (Aku et al., 2018). In our study, the E.
cefotaxime (34%) (table 4). Intermediate susceptibility coli, Klebsiella, and Proteus isolates from neonatal sepsis
pattern (17%) was shown for amikacin by Acinetobacter showed 75%, 60% and 50% resistance to cefotaxime.
isolates. The Proteus isolates from neonates were Another study from India revealed that Enterobacteriacea
sensitive (75%) to amikacin, ceftazidime and showed high resistance (90%) to ciprofloxacin as
sulfamethoxazole. However, these were intermediately compared to meropenem (49%). Resistance to
susceptible (25%) to imipenem and ciprofloxacin. sulfamethoxazole by E. coli and Klebsiella was 69% and
89% respectively (Mitra et al., 2019) . We found that
DISCUSSION neonatal sepsis associated Klebsiella showed resistance to
sulfamethoxazole (80%) and to ciprofloxacin (70%).
Sepsis is major cause of morbidity and mortality in However, the resistance for sulfamethoxazole and
neonates globally ranging from 30-50% in developing ciprofloxacin in E. coli was 37 and 62%, respectively.
countries (Klick and Guins, 2021). Gram negative
bacteria play an important role in causing nosocomial and Neonatal Blood culture is considered “Gold standard” in
non- nosocomial infections (Rasool et al., 2019). Death diagnosis of sepsis but the inadequate amount of blood
rate in neonates comprise of 41% (3.6 million) in children limits the accuracy of test. Other tests like procalcitonin,
below 5 years. About 1 million of these deaths are linked complete blood count and C-reactive protein are useful in
with infectious diseases like pneumonia, neonatal sepsis diagnosis but are not helpful to choose the antibiotic, to
and meningitis (Getabelew et al., 2018). The present start the initial treatment of suspected neonates with
study revealed the occurrence and antimicrobial sepsis (Popescu et al., 2020).
Pak. J. Pharm. Sci., Vol.34, No.5(Suppl), September 2021, pp.1873-1878 1875
Pattern of clinical drug resistance and occurrence of Gram negative bacterial neonatal sepsis at a tertiary care hospital

Table 1: Frequency of Gram-negative bacteria with respect to the age of neonates

Organisms
Total
Klebsiella E. coli Acinetobacter Proteus No Growth
1-4 D 5 4 1 0 20 30
5-8 D 3 2 3 2 33 43
Age of Neonates
9-12 D 1 1 2 2 10 16
13-16 D 1 1 0 0 9 11
Total 10 8 6 4 72 100
Chi-Square Test
Value df Asymp. Sig. (2-sided)
Pearson Chi-Square 18.379a 18 .005
Likelihood Ratio 17.869 6 .007
Linear-by-Linear Association 1.695 1 .193
N of Valid Cases 144
a. 2 cells (16.7%) have expected count less than 5. The minimum expected count is 2.40.

Table 2: Frequency of EOS and LOS in neonates with respect to age

Stage
Total
EOS LOS
1-4 D 23 0 23
5-8 D 37 19 56
Age of Neonates
9-12 D 0 17 17
13-16 D 0 4 4
Total 60 40 100
Chi-Square Test
Value df Asymp. Sig. (2-sided)
Pearson Chi-Square 16.728a 7 .020
Likelihood Ratio 17.217 12 .142
Linear-by-Linear Association .562 1 .453
N of Valid Cases 144
a. 9 cells (45.0%) have expected count less than 5. The minimum expected count is 1.15.

Table 3: Frequency of EOS and LOS in neonates with respect to gender

Stage Total
EOS LOS
Male 24 21 45
Male/Female
Female 36 19 55
Total 60 40 100
Chi-Square Test
Value df Asymp. Sig. (2-sided)
Pearson Chi-Square 23.143a 3 .027
Likelihood Ratio 29.245 3 .004
Linear-by-Linear Association .403 1 .526
N of Valid Cases 144
a. 10 cells (50.0%) have expected count less than 5. The minimum expected count is .94.
EOS= Early Onset Sepsis; LOS= Late Onset Sepsis
Table 4: Antibiotic susceptibility of Gram-negative bacteria isolated from neonatal sepsis
Bacteria IPM% S(n) AMK% S(n) CIP% S(n) CAZ% S(n) CTX% S(n) SXT% S(n)
Klebsiella (n=10) 7(10)=70% 3(10)=30% 3(10)=30% 4(10)=40% 4(10)=40% 2(10)=20%
E. coli (n=8) 5(8)=63% 4(8)=50% 3(8)=38% 2(8)=25% 2(8)=25% 5(8)=63%
Acinetobacter (n=6) 2(6)=34% 1(6)=17% 0(6)=0% 3(6)=50% 2(6)=34% 0(6)=0%
Proteus (n=4) 1(4)=25% 3(4)=75% 1(4)=25% 3(4)=75% 2(4)=50% 3(4)=75%
IPM=Imipenem; AMK= Amikacin; CIP= Ciprofloxacin; CAZ= Ceftazidime; CTX= Cefotaxime; SXT= Sulfamethoxazole

1876 Pak. J. Pharm. Sci., Vol.34, No.5(Suppl), September 2021, pp.1873-1878

 Aqsa Ahmad et al

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