Antibiotic regimens for suspected early neonatal sepsis
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The objectives are to compare antibiotic monotherapies, monotherapy with combination therapy, and combination therapies for empirical treatment of suspected early neonatal sepsis (within 48 hours after birth), for both effectiveness and adverse effects.
Background
Infection remains a major cause of illness and death in the neonatal period (Freedman 1981, La Gamma 1983, Gladstone 1990). Newborn babies have an immature immune system and therefore they may not elicit all signs of infection, and delay in treatment may lead to severe illness or death (Miller 1977,Siegel 1981). Early treatment with antibiotics has been shown to reduce mortality due to sepsis in the neonatal period (Freedman 1981). Early treatment depends on knowledge of risk factors and picking up early signs of infection in this age group (Miller 1977, Siegel 1981). However the signs of infection tend to be non‐specific (Philip 1980). Suspected sepsis is therefore defined as any clinical concern for infection to warrant the starting of intravenous antibiotic therapy before laboratory or microbiological evidence of infection.
Early neonatal sepsis is mainly acquired from mother. Vertical transmission of infection from mother to infant may take place before birth, during labour, or at the time of delivery. Most infants with peripartum acquired sepsis will develop clinical symptoms of sepsis within two days of life. After this period, nosocomial and community acquired infections start to play a bigger role. The bacteria most commonly implicated in early neonatal sepsis are Group B streptococcus and Gram‐negative bacilli, and usually exclude coagulase negative staphylococcus. Neonatal intensive care units or special care baby units tend to choose empirical first line antibiotic therapy that will cover both Gram‐negative and Gram‐positive bacteria. A combination of an aminoglycoside such as gentamicin and a beta‐lactam such as penicillin has been the treatment of choice for early neonatal sepsis in many neonatal intensive care units (NICU).
Aminoglycosides may be associated with important adverse effects and they require frequent monitoring of blood levels. Preterm infants have immature organs and therefore may not tolerate some antibiotics as well as term infants. Further to these significant disadvantages, the majority of treated babies do not have proven sepsis. A recent systematic review looking at empirical treatment for febrile neutropaenia in cancer patients found no significant difference between using beta‐lactam monotherapy or beta‐lactam and aminoglycoside combination, although there was a slight advantage in using third generation cephalosporins (Paul 2002). On the other hand the use of broad spectrum antibiotics in neonates may alter gut flora and may also increase antibiotic resistance in the unit (Kalenic 1993). Alteration of intestinal flora or sterilisation of the gut with these antibiotics may increase the risk of developing necrotising enterocolitis after stopping treatment (Kenyon 2001).
Objectives
The objectives are to compare antibiotic monotherapies, monotherapy with combination therapy, and combination therapies for empirical treatment of suspected early neonatal sepsis (within 48 hours after birth), for both effectiveness and adverse effects.
Methods
Criteria for considering studies for this review
Types of studies
Randomised and quasi‐randomised controlled trials, published and unpublished, will be considered for this review. For studies published in abstract form, the authors will make every attempt to obtain full details. Studies with cluster randomisation will be excluded.
Types of participants
Newborn babies from birth to 48 hours of life, requiring treatment in hospital or community for any suspected neonatal sepsis, regardless of gestation at birth.
Types of interventions
Comparison between the following intravenous antibiotic regimens:
a) Any antibacterial monotherapy versus other monotherapy:
aminoglycoside
beta‐lactam
beta‐lactam plus betalactamase inhibitors
glycopeptide
b) Any antibacterial monotherapy versus combination therapy of any antibiotic listed above
c) Any antibacterial combination therapy versus another antibacterial combination therapy
Types of outcome measures
1) Primary outcomes:
1) Mortality in the first 28 days of life
2) Mortality up to the time of discharge from hospital
3) Treatment failure defined as the need to change empirical antibiotic therapy
4) Bacteriological resistance (isolated organisms resistant to assigned empirical treatment)
2) Secondary outcomes:
1) Adverse effects:
1) Superinfection (Clinical signs of sepsis with isolation of a new pathogen or the same
pathogen with different susceptibility).
2) Colonisation with bacteria resistant to allocated empirical antibiotic in the follow up
period
3) Necrotising enterocolitis during or after treatment, Bells criteria 2 (Bell 1978)
4) Serious nephrotoxicity (causing deviation from protocol, e.g. changing antibiotics)
5) Ototoxicity defined as a failed hearing test
6) Serious hepatotoxicity (resulting in deviating from protocol)
7) Anaphylactic reactions in the treated infant (resulting in deviating from protocol)
2) Length of hospital stay
Search methods for identification of studies
The following terms will be used to search electronic databases: (antibiot* OR antimicrob* OR lactam*OR aminoglycoside* OR glycoprotein) AND (sepsis OR septic* OR Infect* OR bacter* OR (gram near negative)). The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2003) will be searched using the above terms with restriction to neonates or infants. MEDLINE search (PubMed 1966 to August 2003) will be restricted to Clinical Trials, All Infant, and Human, applying the same search terms. Further searches will be performed in EMBASE (1980 to September 2003) for pharmaceutical publications and ZETOC (1993 to August 2003) for abstracts of scientific conferences/symposia. No language restriction will be applied. References from identified studies will be cross‐checked for possible additional studies. Pharmaceutical companies will be contacted for any unpublished data.
Data collection and analysis
The abstract of each reference generated by the search will be examined by the reviewers for inclusion criteria and where relevant a full article will be obtained. The relevant studies will be reviewed for methodological quality. Criteria for assessing methodological quality will be blinding of randomisation, blinding of intervention, complete follow up, and blinding of outcome measures (The Cochrane Neonatal Review Group Guidelines). The reviewers will discuss areas of disagreement to reach a consensus before analysis of the results.
The reviewers will extract data from included studies. For dichotomous outcomes, treatment effect will be expressed as relative risk, with 95% confidence interval as a measure of uncertainty within the trial. For outcomes measured on a continuous scale, treatment effect will be expressed as mean difference and uncertainty will be measured by standard deviation. If appropriate, meta‐analyses of pooled data from all contributing trials will be performed using a fixed effect model to obtain a typical relative risk or weighted mean difference respectively. Then, in a sensitivity analysis to examine the effect of study quality, the meta‐analyses will be restricted to high quality studies, with lower quality studies being added on to see if they influence any outcome effect. A test for heterogeneity will be performed. The results from this test will be used as a trigger to explore sources of heterogeneity. Subgroup analysis by gestational age, term (>37 weeks) and preterm, with a further subgroup analysis in the preterm group by birth weight (>1500 grams and <1500 grams) will also be considered. Data will be analysed using MetaView 4.2 (Update Software).
