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Establishing a case definition for national and international surveillance of healthcare associated bloodstream infection in neonates

Presented at the Neonatal Society 2006 Summer Meeting (programme).

Modi N1, Doré CJ3, Saraswatula A1, Richards M2, Bamford KB2, Coello R2, Holmes A2

1 Division of Medicine, Imperial College London, London, UK
2 Department of Infectious Diseases, Imperial College London, London, UK
3 MRC Clinical Trials Unit, London, UK

Background and aim: Healthcare associated bloodstream infection (BSI) is a major cause of mortality in neonates and a growing cause of increased costs and adverse long-term sequelae. BSI surveillance, an essential component of infection control, requires an unambiguous case definition, but this has proven problematic given the high proportion of mixed and coagulase negative staphylococcal (CoNS) cultures in neonates. A substantial proportion of these will represent contamination rather than true BSI. In work previously presented to this Society, we recommended the use of a standardised case definition for neonatal BSI. The aim of this study was to establish a pragmatic case definition for neonatal BSI suitable for national and international application.

Setting and methods: We utilised data from 26 neonatal units participating in a UK multicentre, single-blind, randomised controlled trial PROGRAMS (PROphylactic GRAnulocyte Macrophage colony stimulating factor to reduce Sepsis, mortality and later disability in preterm neonates, ISRCTN42553489). Data are captured daily from trial entry within 3 days of birth to 28 days or death of the infant if earlier. Blood cultures are obtained at the discretion of the attending clinician. Daily data include the results of blood cultures and CRP, and the objective evaluation of 12 pre-defined clinical signs widely held to be suggestive of BSI. We analysed daily data for each infant recruited up to the onset of the first positive blood culture. The prevalence of each of the 12 clinical signs and acute rise in CRP was determined together with the sensitivity, specificity, odds ratio and positive predictive value of each individual sign for a positive blood culture. We gave a weight of 1 to each clinical sign selected at the 5% significance level on univariate analysis, on the assumption that they were equally important, and calculated the total number of clinical signs present for each baby for each day. We calculated the predicted probability of a positive blood culture at sequential numbers of clinical signs and derived the sensitivity and specificity for each cut-off. The number of clinical signs with the greatest accuracy for predicting a positive blood culture was determined in order to incorporate this into the case definition for CoNS or other skin commensal, and mixed growth BSI. We then tested the case definition in an independent data set from a single hospital. The PROGRAMS trial is approved by the South Thames Multicentre Research Ethics Committee; the use of clinical data in the independent dataset was approved by the Hammersmith Hospitals Trust Caldicott Guardian.

Results: Data were analysed from the first 220 infants recruited to PROGRAMS from 26 neonatal units. There were 99 positive blood cultures and 3954 days of observations in this data set. We excluded 2 of the12 predefined clinical signs as poorly predictive. In the independent data set 561 blood cultures were obtained in 471 infants admitted to a single neonatal unit. There were 213 positive and 348 negative blood cultures. When validated in this independent data set we found that the presence of 3 or more clinical signs had the best accuracy for a positive blood culture (specificity 76.2%; sensitivity 61.5% for all positive blood cultures, 46.9% for CoNS positive blood cultures and 78.2% for blood cultures yielding a recognised pathogen). The addition of an acute C-reactive protein response increased specificity but decreased sensitivity. Overall accuracy was better with 3 or more clinical signs without a CRP response.

Conclusion: The growth of a recognised pathogen in pure culture or, in the case of a mixed growth or growth of a skin commensal, the added requirement for the acute onset of 3 of 10 predefined clinical signs, offers a simple case definition for national and international neonatal BSI surveillance.

Acknowledgements: We gratefully acknowledge the contributions of the PROGRAMS trial investigators and Ian de Vega, Hammersmith Hospitals Trust neonatal data co-ordinator.

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