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Antibiotic regimens for suspected late onset sepsis in newborn infants

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Authors

Gordon A, Jeffery HE

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs


Dates

Date edited: 24/05/2005
Date of last substantive update: 01/03/2005
Date of last minor update: 21/03/2005
Date next stage expected 30/11/2006
Protocol first published: Issue 4, 2003
Review first published: Issue 3, 2005

Contact reviewer

Dr Adrienne Gordon

Neonatal Fellow
Royal Prince Alfred Hospital
Missenden Road
Sydney
NSW AUSTRALIA
2050
Telephone 1: 00 61 2 9515 6111 extension: 57039
Facsimile: 00 61 2 9550 4375

E-mail: adrienne.gordon@email.cs.nsw.gov.au

Secondary contact person's name: Prof Heather Jeffery

Contribution of reviewers

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.

Sources of Support

Internal sources of support

RPA Newborn Care, RPA Hospital, NSW, AUSTRALIA

External sources of support

  • None noted.

What's new

Date / Event Description

History

Date / Event Description

Synopsis

  • Synopsis pending

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 strategy

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 & 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.

Reviewers' 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.

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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). Nosocomial 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.

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 strategy 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.

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Methods of the review

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 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 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.

Description of studies

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.

Methodological quality of 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.

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Results

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.

Discussion

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) 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 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. 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). 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.

Reviewers' 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 research 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.

Potential conflict of interest

The review authors have no conflict of interest to declare

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Characteristics of studies

Characteristics of Included Studies

Study Methods Participants Interventions Outcomes Notes Allocation concealment
Miall-Allen 1988 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
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
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

Mortality
Treatment failure
Antibiotic resistance
B

Characteristics of excluded studies

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
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

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References to studies

Included studies

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.

Excluded studies

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.

* indicates the primary reference for the study

Other references

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. In: The Cochrane Database of Systematic Reviews, Issue 1, 2000.

Feigin 1977

Feigin RD. Bacterial infections in the newborn infant. In: 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. In: 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.

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.

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.

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.

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.

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

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Weintzen RL, McCracken GH. Pathogenesis and management of neonatal sepsis and meningitis. In: Current Problems in Pediatrics. Vol. VIII. C.V. Mosby Co, 1977:1-61.

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Data and analyses

01 Beta-lactam antibiotic/s versus combination of beta-lactam plus aminoglycoside

Comparison or outcome Studies Participants Statistical method Effect size
01.01 Mortality prior to discharge 1 24 RR (fixed), 95% CI 0.17 [0.01, 3.23]
01.02 Treatment failure 1 24 RR (fixed), 95% CI 0.17 [0.01, 3.23]
01.03 Antibiotic resistance 0 0 RR (fixed), 95% CI No numeric data

Additional tables

01 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)

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 aztreonam +ampicillin group
32 neonates analysed in the amikacin +ampicillin group

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
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

Notes

  • None noted.

Additional tables

  • None noted.

Amended sections

Cover sheet
Synopsis
Abstract
Background
Objectives
Criteria for considering studies for this review
Search strategy for identification of studies
Methods of the review
Description of studies
Methodological quality of included studies
Results
Discussion
Reviewers' conclusions
Acknowledgements
Potential conflict of interest
References to studies
Other references
Characteristics of Included Studies
Characteristics of excluded studies
Characteristics of ongoing studies
Comparisons, data or analyses
Additional tables and figures

Contact details for co-reviewers

Prof Heather E Jeffery

Head of Department
Neonatal Medicine
Royal Prince Alfred
Missenden Road
Sydney
NSW AUSTRALIA
2050
Telephone 1: 00 61 2 9515 6111 extension: 58899
Facsimile: 00 61 2 9550 4375

E-mail: hjeffery@med.usyd.edu.au

Secondary contact person's name: Dr Adrienne Gordon


The review is published as a Cochrane review in The Cochrane Library, Issue 3, 2005 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in reponse to comments and criticisms, and The Cochrane Library should be consulted for the most recent version of the review.