Indian Pediatr 2010;47: 785-788
Restriction of Cephalosporins and Control of
Producing Gram Negative Bacteria in a Neonatal Intensive Care
Srinivas Murki, Sravanthi Jonnala, Faheemuddin Mohammed and Anupama Reddy
From Departments of Neonatology and Pathology, Fernandez
Hospital, Hyderabad, India.
Correspondence to: Dr Srinivas Murki, Consultant
Neonatologist, Fernandez Hospital, Bogulkunta, Hyderabad, India. Email:
Received: April 23, 2009;
Initial review: June 22, 2009;
Accepted: August 24, 2009.
Published online: 2010, January 1.
This interventional study with historical controls
was conducted to study the effect of cephalosporin restriction on the
incidence of extended spectrum beta-lactamase (ESBL) gram negative
infections in neonates admitted to intensive care unit. All gram
negative isolates from the blood were evaluated for beta lactamase
production. The incidence of ESBL production was compared before (year
2007) and after cephalosporin restriction (year 2008). Thirty two
neonates (3% of NICU admissions) in the year 2007 and fifty six (5.2%)
in the year 2008, had gram negative septicemia. The incidence of ESBL
gram negatives decreased by 22% (47% to 25%, P=0.03). Restriction
of all class of cephalosporins significantly decreased the incidence of
ESBL gram negative infections.
Key words: Cephalosporin, ESBL, Gram negative sepsis, India,
ndiscriminate use of broad spectrum
antibiotics, prolonged courses of antibiotic therapy, dependence on
C-reactive protein, and absence of culture facilities have resulted in
increased incidence of extended spectrum betalactamases (ESBL),
methicillin resistant staphylococci aureus (MRSA) and multi-drug
resistant bacteria(1). Implementation of infection control measures,
restricting the use of broad-spectrum antibiotics, rotation of
antibiotics, and rationalizing the use of antibiotics can decrease
antibiotic resistance(2,3). A few studies done in adult and pediatric
intensive care units reported decreased incidence of ESBL gram negative
infections after cephalosporin restriction(4-6).
This study was conducted in the neonatal intensive care
unit (NICU) of Fernandez Hospital, a tertiary care hospital with a
delivery rate of approximately 4000 births per year. From January 2007 to
December 2008, all neonates admitted to the NICU were eligible for the
study. All neonates suspected to have infections either due to perinatal
risk factors or due to clinical signs were subjected to sepsis screen and
a blood culture was obtained before starting antibiotics. In the year
2007, the empirical antibiotic therapy included cefotaxime or ampicillin
with amikacin. For treating a documented gram-negative organism,
preference was given to cephalosporins over pipericillin-tazobactum,
quinolones and imipenem/meropenem; in that order. From 1 January 2008, the
policy was to restrict cephalosporins; ampicillin with amikacin was used
for empiric antibiotic therapy. For blood culture positive infections,
preference was given to quinolones, pipericillin-tazobactum, imipenem/meropenem
over cephalosporins; in that order. If a baby had meningitis, cefotaxime/cefaperazone
was the preferred drug.
The primary outcome was the incidence of ESBL
gram-negative infections. The secondary outcome was gram-negative
resistance to cefotaxime, amikacin, ciprofloxacin and
pipericillin-tazobactum. Blood cultures were done with Bact Alert.
Antibiotic susceptibilities were determined by disc diffusion method(7).
Organisms showing resistance to ceftazidime, cefotaxime and ceftriaxone
were taken as indicators of ESBL production. To confirm the presence of
ESBL, double disc synergy test was performed.
The clinical and laboratory data of all eligible babies
was collected prospectively in a structured proforma for the year 2008.
The data for the year 2007 was collected retrospectively from the
computerized clinical database, case files and the laboratory records. If
more than one gram-negative organism was isolated in a baby, only the
resistant organism was included in the study.
The primary and secondary outcomes were compared
between years before and after antibiotic policy change. P<0.05 was
considered significant. The institute ethics committee approved the study.
One thousand and forty six neonates were admitted to
the NICU in the year 2007 and 1074 neonates in the year 2008. Among the
admissions; the sex ratio, proportion of premature infants, VLBW infants,
and infants requiring ventilation (synchronized ventilation or CPAP) were
similar during the two epochs (Table I). However, more
babies received CPAP and central venous lines in 2008.
Baseline Variables of NICU Admissions
VLBW=very low birth weight; CPAP = continuous positive airway
Similar proportion of NICU admissions were on
antibiotics during the two epochs. In the year 2008, there was nearly
five-fold decrease in the use of cephalosporins and nearly two folds
increase in the use of ampicillin and ciprofloxacin compared to the year
2007 (Table II).
Antibiotic Usage Profile of NICU Admissions
Thirty-two neonates (3% of NICU admissions) in the year
2007 and fifty-six (5.2%) in the year 2008 had gram-negative septicemia;
the mean weight (1592 ±719g vs 1618 ± 856g, P value 0.88),
mean gestation (32 ± 3 wks vs 32 ± 3.6 wks, P = 0.84) and
the age of onset of infections (5.2 ± 4 d vs 7.6 ± 9 d, P=0.17)
were similar in the two groups. During the study period (both the epochs)
the organisms isolated were Klebsiella pneumoniae (n
= 44), Pseudomonas aeruginosa (n=16), E.coli (n=13),
Enterobacter sp (n=12) and others (n=3). After
cephalosporin restriction, the prevalence of ESBL gram negative organisms
significantly decreased by 22%, cefotaxime resistant gram negatives
decreased by 30% and that of ciprofloxacin resistant gram negatives by
27%. There was no change in the prevalence of gram negatives that are
amikacin resistant or pipericillin-tazobactum resistant, and resistant to
either ampicillin or amikacin (Table III). The need to
upgrade the empiric antibiotics significantly increased in the year 2008
as compared to year 2007 (48% vs. 26% respectively, P <0.0001).
However, change in the antibiotic policy did not affect the mortality [(n=9
(28%) vs. n=13 (23%), P value 0.79] or duration of
hospitalization (18 ± 14 d vs. 23 ± 19 d, P = 0.20) among
infants with gram negative sepsis.
Antibiotic Susceptibility of Gram Negative Infections and ESBL
ESBL: Extended Spectrum b-Lactamase Producing Gram Negative Bacteria; RGN: resistant gram negative bacteria.
This study demonstrated that restricted use of
cephalosporins significantly reduced the incidence of ESBL producing,
cefotaxime resistant and ciprofloxacin resistant gram negatives. This
reduction in ESBL was seen, eventhough the incidence of gram-negative
sepsis was higher. The profile of organisms in our study is similar to
that reported in other Indian studies(8,9). Antibiotic sensitivity before
cephalosporin restriction is also similar to other reports from our
region. In a study from North India, 61.5% of gram negative isolates were
This experience of cephalosporin restriction is similar
to that reported from pediatric and adult intensive care units(4-6). In a
study on adult intensive care patients, 44% reduction in ceftazidime
resistant Klebsiella infection was possible with 80% reduction in
the use of cephalosporin antibiotics(4). In a study on pediatric patients
by Lee, et al.(5), the incidence of ESBL gram negatives decreased
from 39.8% to 22.3% with cephalosporin restriction. Third generation
cephalosporins select for gram-negative bacilli that produce ESBLs, which
render the bacteria resistant to many antibiotics and not just beta-lactams.
Hence, reduced incidence of ESBLs also contributes to reduced resistance
to other antibiotics. In our study, cephalosporin restriction resulted in
27% reduction in ciprofloxacin resistance, in-spite of a two fold increase
in the use of ciprofloxacin.
A major limitation of the study is that it is not a
randomized controlled trial. Many practices in the unit would have changed
with time. In 2008, we used bubble CPAP for early management of RDS in
place of mechanical ventilation, babies were started on aggressive
parenteral nutrition and hence more babies were on central lines.
Antibiotic usage was measured as percent of patients on specific
antibiotics and not as duration of antibiotic days; and we included all
babies with neonatal sepsis and not those only with nosocomial infections.
No change was made in the antibiotic policy given to the mothers.
Contributions: SM designed the study. SJ, AR and FM
collected the data, wrote the manuscript. JS did the lab investigations
and blood cultures. All authors reviewed the manuscript and consented for
Competing interest: None stated.
What This Study Adds?
Cephalosporin restriction leads to a
decrease in the incidence of extended spectrum b-lactamase producing
gram negative bacterial sepsis in a neonatal unit.
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