Coc

Antibiotic regimens for suspected late onset sepsis in
newborn infants (Review)

Gordon A, Jeffery HE
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2012, Issue 5
http://www.thecochranelibrary.com
Antibiotic regimens for suspected late onset sepsis in newborn infants (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ACKNOWLEDGEMENTS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Beta-lactam antibiotic/s versus combination of beta-lactam plus aminoglycoside, Outcome 1
Mortality prior to discharge. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Treatment failure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Antibiotic resistance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
INDEX TERMS
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1
1
2
2
3
3
4
5
6
7
7
8
11
11
12
12
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14
15
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16
[Intervention Review]
Antibiotic regimens for suspected late onset sepsis in

newborn infants
Adrienne Gordon1 , Heather E Jeffery2
1 RPA Newborn Care, RPA Women and Babies, Royal Prince Alfred Hospital, Sydney, Australia. 2 RPA Newborn Care, RPA Women
and Babies, Royal Prince Alfred Hospital and University of Sydney, School of Public Health, Sydney, Australia
Contact address: Adrienne Gordon, RPA Newborn Care, RPA Women and Babies, Royal Prince Alfred Hospital, Missenden Road,
Camperdown, Sydney, NSW, 2050, Australia. adrienne.gordon@email.cs.nsw.gov.au.
Editorial group: Cochrane Neonatal Group.
Publication status and date: Edited (no change to conclusions), published in Issue 5, 2012.
Review content assessed as up-to-date: 1 March 2005.
Citation: Gordon A, Jeffery HE. Antibiotic regimens for suspected late onset sepsis in newborn infants. Cochrane Database of Systematic
Reviews 2005, Issue 3. Art. No.: CD004501. DOI: 10.1002/14651858.CD004501.pub2.
ABSTRACT
Background
Late onset neonatal sepsis (systemic infection after 48 hours of age) continues to be a significant cause of morbidity and mortality.
Early treatment with antibiotics is essential as infants can deteriorate rapidly. It is not clear which antibiotic regimen is most suitable
for initial treatment of suspected late onset sepsis.
Objectives
To compare the effectiveness and adverse effects of different antibiotic regimens for treatment of suspected late onset sepsis in newborn
infants.
Search methods
The standard search strategy of the Cochrane Neonatal Review Group was used. This includes electronic searches of the Cochrane
Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2004), MEDLINE (1966 - Dec 2004), EMBASE
(1980 - Dec 2004) and CINAHL (1982 - Dec 2004), electronic abstracts of Pediatric Academic Society meetings (1996 - Dec 2004)
and previous reviews including cross references (all articles referenced).
Selection criteria
Randomised and quasi randomised controlled trials comparing different initial antibiotic regimens in neonates with suspected late
onset sepsis were evaluated.
Data collection and analysis
Both reviewer authors screened abstracts and papers against the inclusion criteria, appraised the quality of and extracted data from
papers. For dichotomous outcomes, treatment effect was expressed as relative risk and risk difference with 95% confidence intervals.
NNT was calculated for outcomes for which there was a statistically significant reduction in risk difference.
Main results
Thirteen studies were identified as possibly eligible for inclusion. The majority of studies were excluded as they did not separate data
for early and late onset infection. Two studies are still awaiting assessment. Only one small study, in 24 neonates, was included in
this review. It compared beta-lactam therapy with a combination of beta lactam plus aminoglycoside. The study did not meet our
prespecified criteria for good methodological quality. In babies with suspected infection there was no significant difference in mortality
(RR 0.17, 95% CI 0.01 to 3.23) or treatment failure (RR 0.17, 95% CI 0.01 to 3.23). Antibiotic resistance was assessed and there
were no cases in either group.
Authors conclusions
There is inadequate evidence from randomised trials in favour of any particular antibiotic regimen for the treatment of suspected late
onset neonatal sepsis. The available evidence is not of high quality. Although suspected sepsis and antibiotic use is common, quality
research is required to specifically address both narrow and broad spectrum antibiotic use for late onset neonatal sepsis. Future research
also needs to assess cost effectiveness and the impact of antibiotics in different settings such as developed or developing countries and
lower gestational age groups.
PLAIN LANGUAGE SUMMARY

Antibiotic regimens for suspected late onset sepsis in newborn infants
Antibiotics for newborn infants that might have blood infections when more than 48 hours old. Blood infection (sepsis) can make
newborn infants seriously ill or even kill them. Sepsis in newborns more than 48 hours old is called late onset neonatal sepsis; it is
usually caused by bacteria, and sometimes by fungal infection. Doctors often give antibiotics if they suspect this dangerous condition
as it can be difficult to tell if a newborn has late onset neonatal sepsis. Certain antibiotics given for this condition can have serious side
effects, including antibiotic resistance, which can result in worse infection. This Cochrane review examined which antibiotics are best
for treating late onset neonatal sepsis, in terms of effectiveness and side effects. The authors searched the medical literature and found
only one study that met all the criteria the authors were looking for. This study, from 1988, enrolled 28 newborn infants. Some of the
newborns received a beta lactam antibiotic by itself while others got the beta lactam plus another antibiotic, an aminoglycoside. There
were no significant differences between the two kinds of antibiotic treatment in this study. The Cochrane review authors concluded
that there is not enough research to recommend one kind of antibiotic treatment over another for late onset neonatal sepsis.
BACKGROUND
Although advances in neonatal intensive care have led to improved
survival of very low birth weight (VLBW) and extremely premature infants, late onset sepsis (systemic infection after 48 hours of
age) continues to be a significant cause of morbidity and mortality.
The incidence of late onset sepsis increases with both decreasing
birthweight and gestational age, and has been reported as occurring in approximately 25% of VLBW infants (Stoll 2002; Rubin
2002; Isaacs 1996). Infants with the lowest birth weights are also
more likely to have multiple episodes of sepsis (Stoll 2002). In
developing countries infection is estimated to cause 30 - 40% of
neonatal deaths (WHO 1999). The spectrum of organisms responsible for early onset (vertically transmitted) sepsis differs from
that associated with late onset (nosocomial) sepsis. This pattern
becomes apparent from day two onwards (Isaacs 1996). Nosoco-
mial infections are frequently associated with clinical deterioration including increased apnoea or ventilatory requirement, temperature instability, abdominal distension, acidosis, lethargy, septic shock, necrotising enterocolitis, meningitis and death (Craft
1999). The complications of necrotising enterocolitis and meningitis predispose an infant to an increased risk of future neurological impairment (Blair 1982; Waugh 1996; Stoll 2004) and the
mortality from late onset sepsis remains high, at 7 - 10% (Stoll
2002; Isaacs 1996). These infections are often particularly distressing for infants, parents and staff as they affect VLBW infants
who have survived early causes of mortality but remain at risk for
ongoing infection. This risk is secondary to: immature immune
responses, poorly developed skin and mucosal barriers to infection, numerous entry portals for organisms via cannulae, catheters
and endotracheal tubes and continuing exposure to oppurtunistic
organisms during often a prolonged hospital stay.

The range of organisms causing late onset sepsis includes gram positive and gram negative bacteria as well as fungal infection. As bacterial infections predominate, empiric antibiotic regimens focus
on cover for both gram positive and negative bacterial infection.
These antibiotics can be either narrow or broad spectrum in the
range of organisms that they target. The epidemiology of late onset infection differs between developing and developed countries
in the incidence of infection, the organisms responsible, and the
subsequent mortality rates. Historical reviews have also demonstrated that the predominant organisms responsible for neonatal
sepsis have changed with time (Stoll 1996 (a)).
In developing countries, the most common gram positive organisms isolated from neonatal blood cultures taken from babies under
90 days of age are streptococcus pneumoniae, staphylococcus aureus and streptococcus pyogenes. The most frequent gram negative
organisms isolated are E coli and salmonella spp (WHO 1999).
WHO recommend that initial treatment of suspected neonatal
sepsis should be with penicillin and gentamicin. This regimen covers most of the likely organisms but has poor coverage of both
salmonella and the increasingly penicillin resistant staphylococcus
aureus.
In developed countries staphylococcus aureus was previously responsible for the majority of late onset infections in many neonatal units with other commonly isolated organisms being coagulase negative staphylococci, E coli, group B streptococcus, Klebsiella pneumoniae, enterococcus, candida and pseudomonas. Coagulase negative staphylococci(CoNS) have now emerged as the
leading cause of late onset sepsis in almost all developed countries
and account for > 50% of positive blood cultures (Rubin 2002;
Isaacs 1996). As skin commensals, these organisms are also common blood culture contaminants, and there is a lack of consensus as to how to interpret CoNS positive results. In the intensive care setting the vast majority of CoNS are resistant to methicillin and thus infants with suspected late onset infection are
typically treated with empiric broad spectrum antibiotics that include vancomycin (Rubin 2002). There are concerns regarding
unrestricted vancomycin use as a risk factor for the development
of resistant organisms, particularly enterococci (HICPAC 1995).
Its routine use as prophylaxis against nosocomial infection has not
been recommended (Craft 1999). Furthermore, the majority of
pathogens associated with fulminant late onset sepsis (lethal within
48 hours) have been shown to be gram negative organisms with
pseudomonas leading the table (Karlowicz 2000; Gordon 2004
(a)). Therefore, although CoNS are currently the most prevalent
pathogens in late onset sepsis in neonatal intensive care units the
associated mortality is low.
Empiric antibiotic treatment varies between neonatal intensive
care units and countries and there are currently no consensus
guidelines on the choice of empiric antibiotics. There are also no
definitive guidelines on classification of CoNS as true sepsis or

contaminant, the removal of indwelling catheters or the duration
of antibiotics for late onset sepsis. The definition of late onset sepsis varies between trials and for the purpose of this review we will
not include those infants commenced on antibiotics prior to 48
hours of age as the type of organisms and method of transmission
of infection differ.
OBJECTIVES
To compare the effectiveness of different antibiotic regimens for
initial treatment of suspected late onset sepsis (after 48 hours of
age) in newborn infants with respect to mortality, septic shock and
neurodevelopmental outcome. Separate comparisons of pre specified antibiotic regimens defined below were undertaken. Planned
subgroup analyses include very low birth weight (less than approximately 1500 g) or very preterm infants (less than approximately 32 weeks gestation) and developing compared with developed countries.
METHODS
Criteria for considering studies for this review
Types of studies
Randomised and quasi randomised controlled trials comparing
different initial antibiotic regimens in neonates with suspected late
onset sepsis were evaluated
Types of participants
Newborn infants with suspected late onset sepsis commenced on
antibiotics after 48 hours of age
Types of interventions
Different antibiotic regimens for infants in whom a decision has
been made to treat suspected systemic infection. We did not review
antibiotics vs no antibiotics.
The following intravenous antibiotic regimens were to be compared:
1) Beta-lactam antibiotic/s, including:
- penicillins
- cephalosporins
- carbapenems
- monobactams
2) Combination of beta lactam with aminoglycoside
3) Combination of beta lactam with glycopeptide
4) Combination of glycopeptide with aminoglycoside

We planned to assess the following comparisons: 1 versus 2, 1
versus 3 , 1 versus 4, 2 versus 3, 2 versus 4, and 3 versus 4
Types of outcome measures
Primary
1) Mortality prior to discharge from hospital
2) Septic shock (hypotension requiring inotropes and/or coagulopathy and/or acidosis)
3) Neurodevelopmental outcome (validated scales of neurodevelopment before 5 years of age)
Secondary
1) Complications of antibiotic treatment (ototoxicity - validated
hearing test prior to discharge, Nephrotoxicty - renal impairment
post treatment)
2) Complications of sepsis (osteomyelitis, meningitis, NEC, hydrocephalus)
3) Treatment failure - ( failed treatment - for example persistent
positive blood cultures, recurrence or worsening of clinical signs
- that then leads to any modification of the assigned empirical
antibiotic treatment )
4) Subsequent fungal infection (positive blood culture for candida)
5) Infection with antibiotic resistant organisms subsequent to
treatment (positive blood cultures)
6) Colonisation with antibiotic resistant organisms subsequent to
treatment (positive ear/skin/nasal/wound swabs or endotracheal
aspirate or sputum or gastric aspirate)
7) Duration of ventilation (days on intermittent positive pressure
ventilation via endotracheal tube)
8) Duration of hospitalisation (days)
9) Cost analysis of treatment (as defined by study)
Search methods for identification of studies

The standard search strategy of the Cochrane Neonatal Review
Group was used. This includes electronic searches of the Cochrane
Central Register of Controlled Trials (CENTRAL, The Cochrane
Library, Issue 4, 2004), MEDLINE (1966 - Dec 2004), EMBASE
(1980 - Dec 2004) and CINAHL (1982 - Dec 2004) and previous reviews including cross references (all articles referenced). The
search strategy included the following keywords, using the search
fields of abstract, MeSH subject heading, exploded subject heading, publication type, subject heading word, text word, and title: A
search on all fields for [infan* OR newborn* OR neonat* ] AND
sepsis, infection, septicaemia, late onset sepsis, late onset infection and antibiotics or antimicrobials was conducted.
The search was limited to: [random* OR trial* OR comparative
study OR controlled study]. We also searched electronic abstracts
of Pediatric Academic Society meetings (1996 - Dec 2004) and
personal files.
Data collection and analysis

Eligibility of studies for inclusion was assessed independently by
each review author. The criteria and standard methods of the
Cochrane Neonatal Review Group were used to assess the methodological quality of the included trials. Quality of the trials included
was evaluated in terms of allocation concealment, adequate randomisation, blinding of parents or carers and assessors to intervention, and completeness of assessment (intention to treat) in
all randomised individuals (this was defined as yes, no or unsure
for each category). A sensitivity analysis was planned according to
the quality of the trials included. Heterogeneity in the results of
the trials was assessed by calculating a test of heterogeneity (Chi
square). Prespecified subgroup analysis was considered to further
explore any heterogeneity.
Additional information was requested from the authors of both
included and excluded eligible trials to clarify methodology and
results as necessary. A data collection form was used to aid extraction of relevant information and data from each included study.
Each review author extracted the data separately, compared data,
and resolved differences by consensus.
The standard methods of the Neonatal Review Group were used
to synthesise the data. Effects were expressed as relative risk (RR),
risk difference (RD) and 95% confidence intervals (CI) for categorical data, and weighted mean difference (WMD) and 95% CI
for continuous data. The fixed effect model was used for metaanalysis.
Separate comparisons of the following antibiotic regimens were
performed:
1) Beta lactam therapy vs beta lactam plus aminoglycoside
The other pre specified antibiotic comparisons could not be assessed as the studies did not separate data for early and late onset
sepsis, and were excluded.
Subgroup analysis was planned for very low birth weight (less than
1500 g) and/or very preterm infants (less than 32 weeks gestation
or as defined by study) as well as developing vs developed countries.
RESULTS
Description of studies
See: Characteristics of included studies; Characteristics of excluded
studies; Characteristics of studies awaiting classification.
Thirteen studies were identified as possibly eligible for inclusion. Eleven of these studies were excluded (see table of excluded
studies). Babies with suspected late onset neonatal sepsis could
not be separated from those with suspected early onset sepsis
(Adelman 1987; Begue 1997; de Louvois 1992; Fogel 1983;
Gokalp 1991; Haffejee 1984; Hall 1988; Hammerberg 1989;
Marks 1978; Snelling 1983; Wiese 1988). All of these studies except one (Gokalp 1991) were randomised and controlled. One
study randomised the infants in the suspected early onset sepsis

group, but not those in the suspected late onset group (Snelling
1983). One study was originally published in French and required
translation into English (Begue 1997). The authors of the excluded studies have been contacted (see acknowledgements) and
one study (de Louvois 1992) is awaiting further assessment regarding separate data for babies with suspected early onset and late
onset sepsis.
Two small studies (Umana 1990; Miall-Allen 1988) were eligible
for inclusion. Both these studies enrolled neonates with suspected
late onset sepsis.
Umana 1990 enrolled 147 neonates to receive either two beta
lactam antibiotics (aztreonam and ampicillin) or combination
therapy with a beta lactam plus aminoglycoside (ampicillin and
amikacin). They excluded 79 infants without proven infection
from analysis, plus a further eight infants, and reported outcomes
for 60 neonates with confirmed bacterial infection. The authors
of this study confirmed that the study population were neonates
more than 48 hours of age. Because of the post-randomisation
exclusion of babies without documented infection, which represented 59% of enrolled babies, this study is not currently included
in this review but is awaiting further assessment.
The one included study (Miall-Allen 1988) enrolled 28 neonates
48 hours of age or older and compared beta lactam monotherapy
(Timentin) with combination therapy comprising beta lactam plus
aminoglycoside (Flucloxacillin and Gentamicin). They analysed
outcomes for 24 neonates. Three babies were excluded as they
had a diagnosis other than sepsis (e.g. congenital heart anomaly)
and one was excluded following an incorrect laboratory report.
Miall-Allen 1988 looked at the outcomes of mortality, treatment
failure and the development of antibiotic resistance. It did not
assess any other adverse effects of antibiotic treatment. It included
hypersensitivity in the protocol as a reason to stop intervention
therapy (Timentin) although the nature of any reaction is not
described. The study is described in more detail in the table of
included studies.
Our protocol intended to assess six different comparisons of antibiotic therapy. However, we were only able to assess one comparison from the included study, beta lactam therapy versus beta
lactam plus aminoglycoside. We were unable to compare the following:
Beta lactam therapy vs beta lactam plus glycopeptide
Beta lactam therapy vs aminoglycoside plus glycopeptide
Beta lactam plus aminoglycoside vs beta lactam plus glycopeptide
Beta lactam plus aminoglycoside vs aminoglycoside plus glycopeptide
Beta lactam plus glycopeptide vs aminoglycoside plus glycopeptide
Primary Outcomes:
01) Mortality prior to discharge
There were two deaths in total in Miall-Allen 1988 with both
deaths in the beta lactam plus aminoglycoside group (flucloxacillin
plus gentamicin). There was no significant difference in mortality
(relative risk 0.17, 95% confidence interval 0.01 to 3.23).
The study did not evaluate the other two pre-specified primary
outcomes of septic shock and neurodevelopmental outcome.
Secondary Outcomes:
02) Treatment Failure
Miall-Allen 1988 assessed treatment failure as worsening of clinical condition and/or death. There was no significant difference
in treatment failure between the groups (relative risk 0.17, 95%
confidence interval 0.01 to 3.23).
03) Antibiotic Resistance
Miall-Allen 1988 assessed antibiotic resistance in organisms isolated from blood cultures and documented no cases in either
group. The study did not report antibiotic resistance in organisms
from superficial sites, i.e. colonisation.
The study did not assess our other pre-specified secondary outcomes: complications of antibiotics treatment e.g. ototoxicity and
nephrotoxicity, complications of sepsis (osteomyelitis, NEC, hydrocephalus), duration of ventilation or hospital stay and cost analysis of treatment.
Data were not available for any sub group analysis by gestational
age or birthweight.
Risk of bias in included studies

Miall-Allen 1988 was randomised, but did not report the method
of randomisation. The method of allocation and its concealment
were not stated. Blinding of interventions or outcomes was also
not documented. The study looked at short term outcomes and
accounted for all neonates in intervention and control groups. The
study did not meet our pre-defined criteria for good methodology
and the planned sensitivity analysis according to methodological
quality could not be performed.
Effects of interventions
DISCUSSION
This review had to exclude the majority of detected studies. Many
of the possibly eligible studies were performed in the 1980s and
one in 1978. Although the distinction between early and late onset
sepsis in terms of pathogenesis and organisms had been previously
described (Weintzen 1977; Feigin 1977) the trials performed did
not separate entry and outcome data accordingly. The organisms
responsible for causing neonatal sepsis have changed over time
with both the use of antibiotics and the introduction of neonatal
intensive care (Freedman 1981; McCracken 1966; Klein 1990).
In early onset infection, sepsis is acquired from the mother, usually
secondary to ascending infection, and babies are often systemically

infected at delivery. In contrast, in late onset (nosocomial) infections, the organism first colonises the baby and only later invades
to cause sepsis (Isaacs 1991). Increasing survival of smaller, more
premature infants leads to increased rates of nosocomial infection
(Stoll 1996 (a); Stoll 2002; Zafar 2001). Studies have documented
the timing of onset of neonatal infection and the related organisms
(Isaacs 1996; Stoll 1996 (a); Stoll 1996 (b)). The authors believe
that the distinction between early and late infection is an important one and subsequently directs distinct treatment and prevention strategies.
This review found only two studies that specifically compared antibiotic regimens for suspected late onset neonatal sepsis. Both assessed beta-lactam therapy compared with a combination of betalactam plus aminoglycoside. One study, however, excluded infants
post randomisation who did not have documented sepsis and only
reported outcomes for the babies with confirmed infection. Therefore, this study is not currently included, but the authors of the
study have agreed to try and access the data for the excluded babies. The included study was randomised. There was no blinding
of interventions and outcome measurements, and the outcomes
were only short term. The validity of the results is affected by the
methodological quality of the included trial.
There were no significant differences in mortality (RR 0.17, 95%
CI 0.01 to 3.23) or treatment failure (RR 0.17, 95% CI 0.01 to
3.23) between the groups. Antibiotic resistance was assessed and
there were no cases in either group. The included trial may be too
small to have shown significant differences in important outcomes
such as mortality.
As there was so little data available for this review the authors
also analysed the data for the Umana 1990 study which reported
outcomes for the babies with confirmed infection only. This was
with the aim of providing the information obtained for readers of
this review to both highlight the lack of data on this subject and
to direct future research . We will be unable to include the study
and pool the data until the outcomes for the babies with suspected
infection are known (Please see table of studies awaiting assessment
Table 1). It is important to note that the types of infants in the
studies may have been quite different with one study having been
performed in a Maternity Hospital and the other in a Childrens
Hospital. Both studies took place more than 15 years ago and some
of the antibiotics used are not in common use in NICUs today.
Umana 1990 reported outcomes of only the 60 randomised patients with confirmed sepsis. In babies with confirmed infection
there was no significant difference in mortality (RR 0.65, 95%
CI 0.21 to 2.00), however, there was a non-significant trend to a
reduction in treatment failure (RR 0.25, 95% CI 0.06 to 1.08;
RD -0.21, 95% CI -0.39 to -0.03) in the beta-lactam group. They
found that significantly fewer infants failed to obtain bacteriologic
cure in the betalactam group (relative risk 0.24; 95% confidence
interval 0.08 to 0.77; risk difference -0.33; 95% confidence interval -0.54 to -0.12). The trend to less treatment failure and the
significant difference in bacteriologic cure are possibly due to the
use of aztreonam in this study. The commonest isolate in their
infants was pseudomonas aeruginsoa and there were more infants
with this organism in the amikacin plus ampicillin group. These
infants had lower bactericidal titres against pseudomonas than the
infants in the aztreonam plus ampicillin group. Aztreonam provides excellent Pseudomonas cover but little or no gram positive
cover.
There is insufficient evidence from randomised trials at present
to suggest that any antibiotic regimen is superior than another in
the treatment of suspected late neonatal sepsis. This review has,
however, highlighted a clear lack of research into the benefits and
risks of empiric antibiotic regimens in the treatment of suspected
late onset sepsis.
Late onset neonatal sepsis is mainly acquired nosocomially. Prevention, therefore, is ideal but despite optimal handwashing, staffing
and NICU design, premature infants will continue to develop late
onset infection secondary to immature immune responses, invasive devices and opportunistic infections. Knowledge and surveillance of the organisms present in a Neonatal Intensive Care Unit
may help clinicians to choose the right antibiotic for treating and
preventing sepsis. Pseudomonas infection, for example, has an extremely high mortality (Gordon 2004 (b); Stoll 2002). Neonatal
units with very few babies colonised with Pseudomonas should use
every reasonable means possible to prevent spread of the organism to other babies and commence antibiotics with pseudomonas
cover when invasive sepsis is suspected.
Although surveillance of organisms is mandatory it does not document the harms of treatment. The real difficulty in neonatal infection is in choosing appropriate empiric antibiotic regimens as
many neonates with suspected infection are not actually infected.
These regimens are typically broad spectrum to cover both gram
positive and gram negative bacteria. However, the use of such antibiotic regimens may contribute to the future development of resistant organisms in the neonatal unit. This review was unable to
assess other long term harms of treatment such as hearing loss.
AUTHORS CONCLUSIONS
Implications for practice
There is no evidence from randomised trials in favour of any particular antibiotic regimen for the treatment of suspected late onset
neonatal sepsis
Implications for research

There is a lack of studies that compare different antibiotic regimens for treating suspected late onset neonatal sepsis. More re-
search is needed into narrow versus broad spectrum antibiotic regimens for suspected late onset infection and particularly into the
harms of treatment, both short and long term. In developed countries where coagulase negative staphylococcus is the commonest
late onset infection, trials may wish to compare regimens with
and without vancomycin plus an aminoglycoside. In developing
countries where broad spectrum antibiotic cover is common, ongoing surveillance of types of organisms and increasing antibiotic
resistance is particularly important to then direct randomised trials. Any future research also needs to assess cost effectiveness and
the impact of antibiotics in different settings such as developed or
developing countries and lower gestational age groups.
ACKNOWLEDGEMENTS
The authors would like to acknowledge the letters and emails received so far from the authors of both included and excluded studies. Specifically we would like to thank: Prof George McCracken,
Dr Carla Odio, Dr Ole Hammerberg, Dr John De Louvois, Dr
Mike Hall, Dr Raymond Adelman, Dr Mel Marks and Prof Pierre
Begue.
REFERENCES
References to studies included in this review

Miall-Allen 1988 {published data only}
Miall-Allen VM, Whitelaw AGL, Darrell JH. Ticarcillin
plus clavulanic acid (Timentin) compared with standard
antibiotic regimes in the treatment of early and late neonatal
infections. British Journal of Clinical Practice 1988;42:
2739.
References to studies excluded from this review

Adelman 1987 {published data only}
Adelman RD, Wirth F, Rubio T. A controlled study of
the nephrotoxicity of mezlocillin and gentamicin plus
ampicillin in the neonate. Journal of Pediatrics 1987;111:
88893.
Begue 1997 {published data only}
Begue P, Astruc J, Francois P, Floret D. Comparison of
ceftriaxone and cefotaxime in severe pediatric bacterial
infections: A multicentre study. Medecine et Maladies
Infectieuses 1997;27:3006.
Fogel 1983 {published data only}
Fogel D, Farfel L, Miskin A, Mogilner BM. Comparison
between the combination of azlocillin-gentamicin and
ampicillin-gentamicin in the treatment of a nursery
population. The Israel Journal of Medical Science 1983;19:
100915.
Gokalp 1991 {published data only}
Gokalp AS, Oguz A, Gultekin A, Icagasioglu D. Neonatal
sepsis in Turkey: The comparison between penicillin
plus aminoglycoside and ampicillin plus third-generation
cephalosporin chemotherapies. Materia Medica Polona
1991;23:2268.
Haffejee 1984 {published data only}
Haffejee IE. A therapeutic trial of cefotaxime versus
penicillin-gentamicin for severe infections in children.
Journal of Antimicrobial Chemotherapy 1984;14 supplement
B:14752.
Hall 1988 {published data only}
Hall MA, Ducker DA, Lowes JA, McMichael, Clarke P,
Rowe D, Gordon A, Cole DS. A randomised prospective
comparison of cefotaxime versus netilmicin/penicillin for

treatment of suspected neonatal sepsis. Drugs 1988;35
(supplement 2):16977.
Hammerberg 1989 {published data only}
Hammerberg O, Kurnitzki C, Watts J, Rosenbloom D.
Randomized trial usingh piperacillin versus ampicillin and
amikacin for treatment of premature neonates with risk
factors for sepsis. European Journal of Clinical Microbiology
and Infectious Diseases 1989;8:2414.
Marks 1978 {published data only}
Marks S, Marks MI, Dupont C, Hammerberg S. Evaluation
of three antibiotic programs in newborn infants. Canadian
Medical Association Journal 1978;118:65962.
Snelling 1983 {published data only}
Snelling S, Hart CA, Cooke RW. Ceftazidime or gentamicin
plus benzylpenicillin in neonates less than forty-eight hours
old. Journal of Antimicrobial Chemotherapy 1983;12:3536.
Wiese 1988 {published data only}
Wiese G. Treatment of neonatal sepsis with ceftriaxone/
gentamicin and with azlocillin/gentamicin: a clinical
comparison of efficacy and tolerability. Chemotherapy 1988;
34:15863.
References to studies awaiting assessment

de Louvois 1992 {published data only}
de Louvois J, Dagan R, Tessin I. A comparison of
ceftazidime and aminoglycoside based regimens as empirical
treatment in 1316 cases of suspected sepsis in the newborn.
European Journal of Pediatrics 1992;151:87684.
Umana 1990 {published data only}
Umana MA, Odio CM, Castro E, Salas JL, McCracken GH
Jr. Evaluation of aztreonam and ampicillin vs. amikacin
and ampicillin for treatment of neonatal bacterial infections.
Pediatric Infectious Disease Journal 1990;9:17580.
Additional references
Blair 1982
Blair E, Stanley FJ. An epidemiological study of cerebral
palsy in Western Australia, 1956-1975. III: Postnatal
aetiology. Developmental Medicine and Child Neurology
1982;24:57585.
Craft 1999
Craft AP, Finer NN, Barrington KJ. Vancomycin for
prophylaxis against sepsis in preterm neonates. The
Cochrane Database of Systematic Reviews 2000, Issue 1.
[DOI: 10.1002/14651858.CD001971]
Feigin 1977
Feigin RD. Bacterial infections in the newborn infant.
Neonatal-Perinatal Medicine. Second Edition. CV Mosby,
1977.
Freedman 1981
Freedman RM, Ingram DL, Gross I, Ehrenkranz RA,
Warshaw JB, Baltimore RS. A half century of neonatal
sepsis at Yale: 1928 - 1978. American Journal of Disease in
Childhood 1981;135:1404.
Gordon 2004 (a)
Gordon A, Isaacs D. Late onset infection and the role of
antibiotic prescribing policies. Current Opinion in Infectious
Diseases 2004;17:2316.
Gordon 2004 (b)
Gordon A, Isaacs D. Late onset gram negative infection in
Australia and New Zealand 1992 - 2002. Perinatal Society
of Australia and New Zealand 8th Annual Congress. 2004.
HICPAC 1995
Hospital Infection Control Practices Advisory Committee
(HICPAC). Recommendations for preventing the spread
of vancomycin resistance. Infection Control and Hospital
Epidemiology 1995;16:105113.
Isaacs 1991
Isaacs D, Moxon ER. Neonatal Infections. First Edition.
Butterworth-Heinemann Ltd, 1991:112.
Isaacs 1996
Isaacs D, Barfield C, Clothier T, Darlow B, Diplock R,
Ehrlich J, et al.Late-onset infections of infants in neonatal
units. Journal of Paediatrics and Child Health 1996;32:
15861. [MEDLINE: 97013556; : 9156527]
Karlowicz 2000
Karlowicz M, Buescher E, Surka AE. Fulminant late-onset
sepsis in a neonatal intensive care unit, 1988 - 1997, and the
impact of avoiding empiric vancomycin therapy. Pediatrics
2000;106:138790. [MEDLINE: 20553915; : 11099593]
Klein 1990
Klein JO. Bacteriology of neonatal sepsis. Pediatric Infectious
Disease Journal 1990;9:778.
McCracken 1966
McCracken GH Jr, Shinefield H. Changes in the pattern
of neonatal septicemia and meningitis. American Journal of
Disease in Childhood 1966;112:339.
Rubin 2002
Rubin LG, Sanchez PJ, Siegel J, Levine G, Saiman L,
Jarvis WR, Pediatric Prevention Network. Evaluation and
treatment of neonates with suspected late onset sepsis: A
survey of neonatologists practices. Pediatrics 2002;110:e42.
[MEDLINE: 22247548; : 12359815]
Stoll 1996 (a)
Stoll BJ, Gordon T, Korones SB, Shankaran S, Tyson JE,
Bauer CR, et al.Late-onset sepsis in very low birth weight
neonates: a report from The National Institute of Child
Health and Human Development Neonatal Research
Network. The Journal of Pediatrics 1996;129:6371.
Stoll 1996 (b)
Stoll BJ, Gordon T, Korones SB, Shankaran S, Tyson
JE, Bauer CR, et al.Early-onset sepsis in very low birth
weight neonates: A report from the National Institute of
Child Health and Human Development Neonatal Research
Network. Journal of Pediatrics 1996;129:6371.
Stoll 2002
Stoll BJ, Hansen N, Fanaroff AA, Wright L, Carlo
WA, Ehrenkranz RA, et al.Late-onset sepsis in very low
birth weight neonates: the experience of the NICHD
Neonatal Research Network. Pediatrics 2002;110:28591.
[MEDLINE: 22155756; : 12165580]
Stoll 2004
Stoll B, Hansen N, Fanaroff AA, Wright LL, Carlo WA,
Ehrenkranz RA, Lemons JA, et al.To tap or not to tap: high
likelihood of meningitis without sepsis among very low
birth weight infants. Pediatrics 2004;113:11816.
Waugh 1996
Waugh J, OCallaghan M, Tudehope D, Mohay HA, Burns
YR, Gray PH. Prevalence and aetiology of neurological
impairment in extremely low birthweight infants. Journal of
Paediatrics and Child Health 1996;32:1204.
Weintzen 1977
Weintzen RL, McCracken GH. Pathogenesis and
management of neonatal sepsis and meningitis. Current
Problems in Pediatrics. Vol. VIII, C.V. Mosby Co, 1977:
161.
WHO 1999
WHO Young Infants Study Group. Bacterial etiology of
serious infections in young infants in developing countries.
The Pediatric Infectious Disease Journal 1999;18:S17S22.
Zafar 2001
Zafar N, Wallace C, Kieffer P, Schroeder P, Schootman
M, Hamvas A. Improving survival of vulnerable infants
increases neonatal intensive care unit nosocomial infection
rate. Archives of Pediatrics and Adolescent Medicine 2001;
155:10981104.
Indicates the major publication for the study
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]

Miall-Allen 1988
Methods
Randomised controlled study.

Method and blinding of randomisation is not documented. Blinding of intervention and
outcome is not documented.
All neonates are accounted for; however, 4 infants are excluded from analysis post randomisation
Participants
28 neonates enrolled with suspected or confirmed infection at 48 hours or more after birth
4 patients excluded after randomisation, 3 with different diagnoses and 1 with wrongly
reported organism
Interventions
Betalactam therapy (Timentin) vs betalactam plus aminoglycoside (flucloxacillin and gentamicin)

Timentin 80 mg/kg 12 hourly or 8 hourly if > 2 kg vs. flucloxacillin 25 mg/kg 12 hourly
and gentamicin 2.5 mg/kg 12 hourly
14 neonates randomised to timentin group
14 neonates randomised to flucloxacillin and gentamicin group
Outcomes
Mortality
Treatment failure
Antibiotic resistance
Notes
Risk of bias
Bias
Authors judgement
Support for judgement
Allocation concealment (selection bias)
Unclear risk
B - Unclear
Characteristics of excluded studies [ordered by study ID]
Study
Reason for exclusion
Adelman 1987
The data could not be separated for early and late onset infection
Begue 1997
Fogel 1983
Gokalp 1991
Not randomised
(Continued)
Haffejee 1984
Hall 1988
Hammerberg 1989
Marks 1978
Snelling 1983
Late onset group were not randomised
Wiese 1988
Characteristics of studies awaiting assessment [ordered by study ID]

de Louvois 1992
Methods
Participants
Interventions
Outcomes
Notes
Table 1
Umana 1990
Methods
Participants
Interventions
Outcomes
Notes
Table 1
10
DATA AND ANALYSES
Comparison 1. Beta-lactam antibiotic/s versus combination of beta-lactam plus aminoglycoside
Outcome or subgroup title
No. of
studies
No. of
participants
1 Mortality prior to discharge

2 Treatment failure
3 Antibiotic resistance
1
1
1
24
24
24
Statistical method
Effect size
Risk Ratio (M-H, Fixed, 95% CI)

0.17 [0.01, 3.23]

0.17 [0.01, 3.23]
0.0 [0.0, 0.0]
Analysis 1.1. Comparison 1 Beta-lactam antibiotic/s versus combination of beta-lactam plus

aminoglycoside, Outcome 1 Mortality prior to discharge.
Review:
Comparison: 1 Beta-lactam antibiotic/s versus combination of beta-lactam plus aminoglycoside

Outcome: 1 Mortality prior to discharge
Study or subgroup
Beta-lactam/s
BL + aminoglycoside
n/N
n/N
0/13
2/11
100.0 %
0.17 [ 0.01, 3.23 ]
13
11
100.0 %
0.17 [ 0.01, 3.23 ]
Miall-Allen 1988
Total (95% CI)
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
Total events: 0 (Beta-lactam/s), 2 (BL + aminoglycoside)

Heterogeneity: not applicable
Test for overall effect: Z = 1.18 (P = 0.24)
Test for subgroup differences: Not applicable
0.001 0.01 0.1

Favours BL
10 100 1000
Favours BL + AG
11

aminoglycoside, Outcome 2 Treatment failure.
Review:

Outcome: 2 Treatment failure
Study or subgroup
Beta-lactam/s
BL + aminoglycoside
n/N
n/N
0/13
2/11
100.0 %
0.17 [ 0.01, 3.23 ]
13
11
100.0 %
0.17 [ 0.01, 3.23 ]
Miall-Allen 1988
Total (95% CI)
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
Total events: 0 (Beta-lactam/s), 2 (BL + aminoglycoside)

Test for overall effect: Z = 1.18 (P = 0.24)
0.001 0.01 0.1
Favours BL
10 100 1000
Favours BL + AG

aminoglycoside, Outcome 3 Antibiotic resistance.
Review:

Outcome: 3 Antibiotic resistance
Study or subgroup
Miall-Allen 1988
Total (95% CI)
Beta lactam
BL + aminoglycoside
n/N
n/N
Risk Ratio
Risk Ratio
0/13
0/11
0.0 [ 0.0, 0.0 ]
13
11
0.0 [ 0.0, 0.0 ]
M-H,Fixed,95% CI
M-H,Fixed,95% CI
Total events: 0 (Beta lactam), 0 (BL + aminoglycoside)

Test for overall effect: Z = 0.0 (P < 0.00001)
0.1 0.2
0.5
Favours BL
10
Favours BL + AG
12
ADDITIONAL TABLES
Table 1. Studies awaiting assessment
Study ID
Methods
Participants
Interventions
Outcomes
Results awaited
Umana 1990
Randomised
controlled study.
Randomisation by computer
generated list .Allocation concealment
is not stated. Blinding of intervention
and outcome is not
documented.
All neonates are accounted for however
87 neonates were excluded from analysis and outcomes are
only reported for 60
out of the 147 randomised neonates
147 patients enrolled after 48 hours

of age
79 patients excluded
from analysis by investigators as no documented infection.
8 further patients excluded for one of
the following : 1)
changes from randomised antibiotic
secondary to resistance of organism
cultured 2) parental
request to withdraw
from study
Betalactam
therapy (aztreonam and
ampicillin) vs betalactam plus aminoglycoside (ampicillin
and amikacin)
Overall mortality
Mortality from primary infection
Superinfection
Treatment failure
Bacteriologic cure
Results requested for

the babies without
documented infection in order to permit assessment of
outcomes for all randomised infants
For infants less than

or equal to 2 kg:
Aztreonam 30 mg/
kg 12 hourly (6
hourly if > 7 days)
and ampicillin 50
mg/kg 12 hourly (8
hourly if > 7 days) vs
amikacin 7.5 mg/kg
12 hourly (8 hourly
if > 7 days) and
ampicillin 50 mg /kg
12 hourly (8 hourly
if > 7 days)
For infants > 2 kg:
Aztreonam 30 mg/
kg 8 hourly (6 hourly
if > 7 days) and
ampicillin 50 mg/kg
8 hourly (6 hourly if
> 7 days) vs amikacin
10 mg/kg 12 hourly
(8 hourly if > 7
days) and ampicillin
50 mg /kg 8 hourly
(6 hourly if > 7 days)
Only babies in
whom infection confirmed reported, not
the total number of
neonates enrolled:
28 neonates analysed in the aztre-
13
Table 1. Studies awaiting assessment
(Continued)
onam +ampicillin
group
32 neonates analysed in the amikacin
+ampicillin group
de Louvois 1992
Randomised
controlled
study.
Randomisation by a
computer code from
Glaxo who funded
the study. Allocation concealment by
sealed envelopes. Assesment of intervention and outcomes
were not blinded.
All neonates are accounted for
1316 patients with

suspicion of neonatal sepsis sufficient
to commence antibiotics were enrolled.
Outcomes
analysed for three groups
- proven infection,
clinical +/- lab evidence of infection
and those with initial suspected infection only. First two
groups were analysed
for efficacy and safety and the third
group for safety only
Betalactam therapy
(ceftazidime or ceftazidime + ampicillin)
vs betalactam (ampicillin) + aminoglycoside (gentamicin,tobramycin
or
amikacin). The following doses were used
: 1) Ceftazidime: 50
mg/kg per dose twice
daily (three times
daily if meningitis
suspected). 2) Ampicillin: 100mg/kg per
dose twice daily (
three times daily if
suspected meningitis). 3) Gentamicin/
tobramycin: 2.5 mg/
kg
per
dose 18 hoursly if
<2.5 kg; 12 hourly if
>2.5 kg and < 7days
old; 8 hourly for >2.
5 kg and > 7 days
old. 4) Amikacin: 7.
5 mg/kg per dose 12
hourly
Mortality,
Treatment failure, Bacteriologic cure, Superinfection
Awaiting separate
data for babies with
early and late onset
suspected infection
WHATS NEW
Last assessed as up-to-date: 1 March 2005.
14
Date
Event
Description
17 April 2012
Amended
Additional Table Studies awaiting assessment linked to text
HISTORY
Protocol first published: Issue 4, 2003
Review first published: Issue 3, 2005
Date
Event
Description
12 March 2012
Amended
Additional table linked to text.
16 October 2008
Amended
Converted to new review format.
1 March 2005
New citation required and conclusions have changed
Substantive amendment
CONTRIBUTIONS OF AUTHORS
This review was conceived and coordinated by Adrienne Gordon. Both reviewers developed the search strategies, Adrienne Gordon
undertook the searches. Both reviewers screened abstracts and papers against the inclusion criteria, appraised the quality and extracted
data from papers. Data entry into Revman was done by Adrienne Gordon. Adrienne Gordon contacted authors of included and
excluded studies by mail or email. Both reviewers wrote the review.
DECLARATIONS OF INTEREST
The review authors have no conflict of interest to declare
SOURCES OF SUPPORT
Internal sources
RPA Newborn Care, RPA Hospital, NSW, Australia.
15
External sources
No sources of support supplied
INDEX TERMS
Medical Subject Headings (MeSH)
Infant, Very Low Birth Weight; Aminoglycosides [ therapeutic use]; Bacterial Infections [ drug therapy]; Infant, Newborn; Infant,
Premature; Sepsis [ drug therapy]; Time Factors; beta-Lactams [ therapeutic use]
MeSH check words

Humans
16

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Antibiotic regimens for suspected late onset sepsis in

newborn infants (Review)

Antibiotic regimens for suspected late onset sepsis in

PLAIN LANGUAGE SUMMARY

organisms during often a prolonged hospital stay.

definitive guidelines on classification of CoNS as true sepsis or

Criteria for considering studies for this review

4) Combination of glycopeptide with aminoglycoside

Search methods for identification of studies

Data collection and analysis

study randomised the infants in the suspected early onset sepsis

Risk of bias in included studies

secondary to ascending infection, and babies are often systemically

Implications for research

developing countries and lower gestational age groups.

References to studies included in this review

References to studies excluded from this review

comparison of cefotaxime versus netilmicin/penicillin for

References to studies awaiting assessment

Indicates the major publication for the study

Characteristics of included studies [ordered by study ID]

Randomised controlled study.

Betalactam therapy (Timentin) vs betalactam plus aminoglycoside (flucloxacillin and gentamicin)

Support for judgement

Allocation concealment (selection bias)

Characteristics of excluded studies [ordered by study ID]

Reason for exclusion

Late onset group were not randomised

Characteristics of studies awaiting assessment [ordered by study ID]

DATA AND ANALYSES

Comparison 1. Beta-lactam antibiotic/s versus combination of beta-lactam plus aminoglycoside

Outcome or subgroup title

1 Mortality prior to discharge

Risk Ratio (M-H, Fixed, 95% CI)

0.17 [0.01, 3.23]

Analysis 1.1. Comparison 1 Beta-lactam antibiotic/s versus combination of beta-lactam plus

Antibiotic regimens for suspected late onset sepsis in newborn infants

Comparison: 1 Beta-lactam antibiotic/s versus combination of beta-lactam plus aminoglycoside

0.17 [ 0.01, 3.23 ]

0.17 [ 0.01, 3.23 ]

Total (95% CI)

Total events: 0 (Beta-lactam/s), 2 (BL + aminoglycoside)

0.001 0.01 0.1

Analysis 1.2. Comparison 1 Beta-lactam antibiotic/s versus combination of beta-lactam plus

Antibiotic regimens for suspected late onset sepsis in newborn infants

Comparison: 1 Beta-lactam antibiotic/s versus combination of beta-lactam plus aminoglycoside

0.17 [ 0.01, 3.23 ]

0.17 [ 0.01, 3.23 ]

Total (95% CI)

Total events: 0 (Beta-lactam/s), 2 (BL + aminoglycoside)

0.001 0.01 0.1

Analysis 1.3. Comparison 1 Beta-lactam antibiotic/s versus combination of beta-lactam plus

Antibiotic regimens for suspected late onset sepsis in newborn infants

Comparison: 1 Beta-lactam antibiotic/s versus combination of beta-lactam plus aminoglycoside

Total (95% CI)

0.0 [ 0.0, 0.0 ]

0.0 [ 0.0, 0.0 ]

Total events: 0 (Beta lactam), 0 (BL + aminoglycoside)

147 patients enrolled after 48 hours

Results requested for

For infants less than

Table 1. Studies awaiting assessment