Cochrane Database of Systematic Reviews (Reviews) || Antibiotic regimens for suspected late onset sepsis in newborn infants

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

2005, Issue 3

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.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

14SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

14INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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


[Intervention Review]

Antibiotic regimens for suspected late onset sepsis innewborn infants

Adrienne Gordon1, Heather E Jeffery2

1RPA Newborn Care, RPA Women and Babies, Royal Prince Alfred Hospital, Sydney, Australia. 2RPA 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. [email protected].

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.


A B S T R A C T

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.

1Antibiotic regimens for suspected late onset sepsis in newborn infants (Review)


mailto:[email protected]

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.

P L A I N L A N G U A G E S U M M A R Y

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.

B A C K G R O U N D

Although advances in neonatal intensive care have led to improved

survival of very low birth weight (VLBW) and extremely prema-

ture 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 occur-

ring 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 re-

sponsible 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 deteriora-

tion including increased apnoea or ventilatory requirement, tem-

perature instability, abdominal distension, acidosis, lethargy, sep-

tic shock, necrotising enterocolitis, meningitis and death (Craft

1999). The complications of necrotising enterocolitis and menin-

gitis predispose an infant to an increased risk of future neurolog-

ical 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 dis-

tressing 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 infec-

tion, 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 pos-

itive and gram negative bacteria as well as fungal infection. As bac-

terial 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 on-

set infection differs between developing and developed countries

in the incidence of infection, the organisms responsible, and the

subsequent mortality rates. Historical reviews have also demon-

strated that the predominant organisms responsible for neonatal

sepsis have changed with time (Stoll 1996 (a)).

In developing countries, the most common gram positive organ-

isms isolated from neonatal blood cultures taken from babies under

90 days of age are streptococcus pneumoniae, staphylococcus au-

reus 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 cov-

ers 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 re-

sponsible for the majority of late onset infections in many neona-

tal units with other commonly isolated organisms being coagu-

lase negative staphylococci, E coli, group B streptococcus, Kleb-

siella pneumoniae, enterococcus, candida and pseudomonas. Co-

agulase 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 com-

mon blood culture contaminants, and there is a lack of consen-

sus as to how to interpret CoNS positive results. In the inten-

sive care setting the vast majority of CoNS are resistant to me-

thicillin and thus infants with suspected late onset infection are

typically treated with empiric broad spectrum antibiotics that in-

clude 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 sep-

sis 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.

O B J E C T I V E S

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 spec-

ified antibiotic regimens defined below were undertaken. Planned

subgroup analyses include very low birth weight (less than ap-

proximately 1500 g) or very preterm infants (less than approxi-

mately 32 weeks gestation) and developing compared with devel-

oped countries.

M E T H O D S

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 com-

pared:

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 coagu-

lopathy and/or acidosis)

3) Neurodevelopmental outcome (validated scales of neurodevel-

opment 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, hy-

drocephalus)

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 can-

dida)

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 previ-

ous 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 head-

ing, 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 on-

set 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 method-

ological quality of the included trials. Quality of the trials included

was evaluated in terms of allocation concealment, adequate ran-

domisation, blinding of parents or carers and assessors to inter-

vention, 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 extrac-

tion 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 cate-

gorical data, and weighted mean difference (WMD) and 95% CI

for continuous data. The fixed effect model was used for meta-

analysis.

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 as-

sessed 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.

R E S U L T S

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 inclu-

sion. 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 ex-

cept 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 ex-

cluded studies have been contacted (see acknowledgements) and

one study (de Louvois 1992) is awaiting further assessment re-

garding 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 repre-

sented 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.

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

Our protocol intended to assess six different comparisons of an-

tibiotic therapy. However, we were only able to assess one com-

parison from the included study, beta lactam therapy versus beta

lactam plus aminoglycoside. We were unable to compare the fol-

lowing:

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 glycopep-

tide

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 clin-

ical 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 iso-

lated 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 out-

comes: complications of antibiotics treatment e.g. ototoxicity and

nephrotoxicity, complications of sepsis (osteomyelitis, NEC, hy-

drocephalus), duration of ventilation or hospital stay and cost anal-

ysis of treatment.

Data were not available for any sub group analysis by gestational

age or birthweight.

D I S C U S S I O N

This review had to exclude the majority of detected studies. Many

of the possibly eligible studies were performed in the 1980’s 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) infec-

tions, 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 impor-

tant one and subsequently directs distinct treatment and preven-

tion strategies.

This review found only two studies that specifically compared an-

tibiotic regimens for suspected late onset neonatal sepsis. Both as-

sessed beta-lactam therapy compared with a combination of beta-

lactam 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. There-

fore, this study is not currently included, but the authors of the

study have agreed to try and access the data for the excluded ba-

bies. 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 pa-

tients 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 in-

terval -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 pro-

vides 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. Preven-

tion, 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, inva-

sive devices and opportunistic infections. Knowledge and surveil-

lance 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 ex-

tremely 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 organ-

ism to other babies and commence antibiotics with pseudomonas

cover when invasive sepsis is suspected.

Although surveillance of organisms is mandatory it does not doc-

ument the harms of treatment. The real difficulty in neonatal in-

fection 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 an-

tibiotic regimens may contribute to the future development of re-

sistant organisms in the neonatal unit. This review was unable to

assess other long term harms of treatment such as hearing loss.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

There is no evidence from randomised trials in favour of any par-

ticular antibiotic regimen for the treatment of suspected late onset

neonatal sepsis

Implications for research

There is a lack of studies that compare different antibiotic regi-

mens for treating suspected late onset neonatal sepsis. More re-



search is needed into narrow versus broad spectrum antibiotic reg-

imens for suspected late onset infection and particularly into the

harms of treatment, both short and long term. In developed coun-

tries 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, on-

going surveillance of types of organisms and increasing antibiotic

resistance is particularly important to then direct randomised tri-

als. 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.

A C K N O W L E D G E M E N T S

The authors would like to acknowledge the letters and emails re-

ceived so far from the authors of both included and excluded stud-

ies. 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.

R E F E R E N C E S

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:

273–9.

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:

888–93.

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;27:300–6.

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:

1009–15.

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;23:226–8.

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:147–52.

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):169–77.

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;8:241–4.

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;118:659–62.

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;12:353–6.

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;

34:158–63.

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;151:876–84.

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;9:175–80.

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;24:575–85.

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;135:140–4.

Gordon 2004 (a)

Gordon A, Isaacs D. Late onset infection and the role of

antibiotic prescribing policies. Current Opinion in Infectious

Diseases 2004;17:231–6.

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;16:105–113.

Isaacs 1991

Isaacs D, Moxon ER. Neonatal Infections. First Edition.

Butterworth-Heinemann Ltd, 1991:1–12.

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:

158–61. [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;106:1387–90. [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;112:33–9.

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;129:63–71.

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;129:63–71.

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;110:285–91.

[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;113:1181–6.

Waugh 1996

Waugh J, O’Callaghan 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;32:120–4.

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:

1–61.

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:S17–S22.

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;

155:1098–1104.∗ Indicates the major publication for the study



C H A R A C T E R I S T I C S O F S T U D I E S

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 randomi-

sation

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 gen-

tamicin)

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 The data could not be separated for early and late onset infection

Fogel 1983 The data could not be separated for early and late onset infection

Gokalp 1991 Not randomised

The data could not be separated for early and late onset infection



(Continued)

Haffejee 1984 The data could not be separated for early and late onset infection

Hall 1988 The data could not be separated for early and late onset infection

Hammerberg 1989 The data could not be separated for early and late onset infection

Marks 1978 The data could not be separated for early and late onset infection

Snelling 1983 Late onset group were not randomised

Wiese 1988 The data could not be separated for early and late onset infection

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



D A T A A N D A N A L Y S E S

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

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Mortality prior to discharge 1 24 Risk Ratio (M-H, Fixed, 95% CI) 0.17 [0.01, 3.23]

2 Treatment failure 1 24 Risk Ratio (M-H, Fixed, 95% CI) 0.17 [0.01, 3.23]

3 Antibiotic resistance 1 24 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

A D D I T I O N A L T A B L E S

Table 1. Studies awaiting assessment

Study ID Methods Participants Interventions Outcomes Results awaited

Umana 1990 Randomised

controlled study.

Randomi-

sation by computer

generated list .Allo-

cation concealment

is not stated. Blind-

ing of intervention

and outcome is not

documented.

All neonates are ac-

counted for however

87 neonates were ex-

cluded from analy-

sis and outcomes are

only reported for 60

out of the 147 ran-

domised neonates

147 patients en-

rolled after 48 hours

of age

79 patients excluded

from analysis by in-

vestigators as no doc-

umented infection.

8 further patients ex-

cluded for one of

the following : 1)

changes from ran-

domised antibiotic

secondary to resis-

tance of organism

cultured 2) parental

request to withdraw

from study

Betalactam ther-

apy (aztreonam and

ampicillin) vs beta-

lactam plus amino-

glycoside (ampicillin

and amikacin)

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

Overall mortality

Mortality from pri-

mary infection

Superinfection

Treatment failure

Bacteriologic cure

Results requested for

the babies without

documented infec-

tion in order to per-

mit assessment of

outcomes for all ran-

domised infants



Table 1. Studies awaiting assessment (Continued)

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 con-

firmed reported, not

the total number of

neonates enrolled:

28 neonates anal-

ysed in the aztre-

onam +ampicillin

group

32 neonates anal-

ysed in the amikacin

+ampicillin group

de Louvois 1992 Randomised

controlled study.

Randomisation by a

computer code from

Glaxo who funded

the study. Alloca-

tion concealment by

sealed envelopes. As-

sesment of interven-

tion and outcomes

were not blinded.

All neonates are ac-

counted for

1316 patients with

suspicion of neona-

tal sepsis sufficient

to commence antibi-

otics were enrolled.

Outcomes anal-

ysed for three groups

- proven infection,

clinical +/- lab ev-

idence of infection

and those with ini-

tial suspected infec-

tion only. First two

groups were analysed

for efficacy and sa-

fety and the third

group for safety only

Betalactam therapy

(ceftazidime or cef-

tazidime + ampi-

cillin)

vs betalactam (ampi-

cillin) + aminoglyco-

side (gentamicin,to-

bramycin or

amikacin). The fol-

low-

ing doses were used

: 1) Ceftazidime: 50

mg/kg per dose twice

daily (three times

daily if meningitis

suspected). 2) Ampi-

cillin: 100mg/kg per

dose twice daily (

three times daily if

suspected meningi-

tis). 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.

Mortality, Treat-

ment failure, Bacte-

riologic cure, Super-

infection

Awaiting separate

data for babies with

early and late onset

suspected infection



Table 1. Studies awaiting assessment (Continued)

5 kg and > 7 days

old. 4) Amikacin: 7.

5 mg/kg per dose 12

hourly

W H A T ’ S N E W

Last assessed as up-to-date: 1 March 2005.

Date Event Description

17 April 2012 Amended Additional Table ’Studies awaiting assessment’ linked to text

H I S T O R Y

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

C O N T R I B U T I O N S O F A U T H O R S

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.



D E C L A R A T I O N S O F I N T E R E S T

The review authors have no conflict of interest to declare

S O U R C E S O F S U P P O R T

Internal sources

• RPA Newborn Care, RPA Hospital, NSW, Australia.

External sources

• No sources of support supplied

I N D E X T E R M S

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



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Cochrane Database of Systematic Reviews (Reviews) || Antibiotic regimens for suspected late onset sepsis in newborn infants