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Review
Early onset neonatal sepsis: diagnostic dilemmas and practical management A R Bedford Russell, R Kumar Neonatal Unit, Birmingham Women’s NICU, Birmingham, UK Correspondence to Dr A R Bedford Russell, Neonatal Unit, Birmingham Women’s NICU, Mindelsohn Way, Birmingham B15 2TG, UK; [email protected] Received 28 July 2014 Revised 30 October 2014 Accepted 5 November 2014 Published Online First 25 November 2014
ABSTRACT Early onset neonatal sepsis is persistently associated with poor outcomes, and incites clinical practice based on the fear of missing a treatable infection in a timely fashion. Unnecessary exposure to antibiotics is also hazardous. Diagnostic dilemmas are discussed in this review, and suggestions offered for practical management while awaiting a more rapidly available ‘gold standard’ test; in an ideal world, this test would be 100% sensitive and 100% specific for the presence of organisms. INTRODUCTION Culture-proven early onset neonatal infection is confirmed in 10 mg/L), and decision making at 36 h, regarding duration of antibiotic therapy.5 Studies including two systematic reviews of the likelihood ratios for leucocyte indexes and CRP to predict sepsis have all concluded that there is too much heterogeneity within the studies and no such ideal test or combination of tests.29 30 Leucopenia and neutropenia, as well as high immature to total neutrophil ratio (I:T ratio) are undoubtedly associated with increasing odds of infection (ORs 5.38, 6.84 and 7.90, respectively); however, the test sensitivities for detection of sepsis are low.31 The combination of two normal I:T ratios within 24 h and a negative blood culture has been suggested as indicative of a non-infected neonate, and may be a contributory marker to assist with the decision to stop antibiotics.32 Having reviewed the more recent evidence, NICE evidence update advisory group (NICE EUAG) does not recommend full blood count for the diagnosis of EONS as the indices are insufficiently sensitive to exclude EONS6 (box 2).
Serum procalcitonin Procalcitonin (PCT) is the prehormone of calcitonin, normally secreted by thyroid C-cells, and rises within 3–6 h of exposure to infection. It has been suggested that elevated serum PCT concentrations are more sensitive and specific in the differentiation between neonatal infection and inflammation than CRP and may also differentiate between bacterial and viral infection. In a meta-analysis of 16 studies (1959 neonates), the sensitivity and specificity for diagnosing infection were 81% and 79%, respectively.33 Limitations of the evidence included variation in definition of neonatal sepsis, differences in age and gestation of neonates and a high level of statistical heterogeneity among studies analysed. Hence, NICE EUAG concluded that the value of PCT in diagnosis of infection requires further research, and PCT concentration cannot be recommended within the current guideline (box 3).
Cytokine profiles and neutrophil/monocyte adhesion molecules Multiple cytokines, for example, interleukins 6, 8 and 10, and tumour necrosis factor-α, and leucocyte adhesion molecules, for example, CD64, CD11b, have been studied for diagnosis of neonatal sepsis. All lack sufficient sensitivity and specificity to be recommended as diagnostic tools for EONS.14
Antimicrobial therapy Antibiotic therapy drives antibiotic resistance and also alters the types of colonising microbial flora, especially in the gut leading to skewing of immune development. E coli EONS has, at best, remained stable in the USA, but approximately 82% of E coli isolates are resistant to amoxicillin or gentamicin in preterm infants.2 Because gut flora drive the nascent immune system, peripartum antibiotic exposure is increasingly recognised as a
major driver of immune dysregulation, resulting in an increasing incidence of atopy and asthma in childhood.4 Antibiotic therapy should be stopped after 36 h if cultures are negative, if two CRP measurements are negative5 and if there are no further signs of infection. Alternatively, when there is a suspicion that clinical progress is suboptimal, consideration should always be given to an empiric change of antibiotic therapy to include a broader spectrum of pathogens. A multiple logistic regression analysis revealed that empiric treatment failure of EONS could be predicted at 24 h using the following variables: need for vasoactive treatment (OR 2.83 (1.21 to 6.66)); WBC 20 000 per mm3 on day 1 (2.51 (1.09 to 5.81)); I:T ratio >0.2 on day 1 (2.79 (1.10 to 7.11)) and platelet count per 10 000 mm−3 increase on day 1 (0.92 (0.86 to 0.98)).34 Such analyses should be validated in other datasets but have the potential to improve neonatal outcome by ensuring that appropriate antibiotics are used as early as possible. Once a bacterium is identified, the antibiotic regimen should be targeted appropriately. An initial gentamicin dose of 5 mg/kg regardless of gestation has been recommended by NICE CGDG5 but not universally adopted by UK neonatologists, who have concerns regarding renal clearance of gentamicin in very immature babies. If a second dose is required, it is recommended that this should be given at 36 h, with a trough level immediately prior to the second dose, and adjustment of the dose to achieve a trough concentration of
Review
Early onset neonatal sepsis: diagnostic dilemmas and practical management A R Bedford Russell, R Kumar Neonatal Unit, Birmingham Women’s NICU, Birmingham, UK Correspondence to Dr A R Bedford Russell, Neonatal Unit, Birmingham Women’s NICU, Mindelsohn Way, Birmingham B15 2TG, UK; [email protected] Received 28 July 2014 Revised 30 October 2014 Accepted 5 November 2014 Published Online First 25 November 2014
ABSTRACT Early onset neonatal sepsis is persistently associated with poor outcomes, and incites clinical practice based on the fear of missing a treatable infection in a timely fashion. Unnecessary exposure to antibiotics is also hazardous. Diagnostic dilemmas are discussed in this review, and suggestions offered for practical management while awaiting a more rapidly available ‘gold standard’ test; in an ideal world, this test would be 100% sensitive and 100% specific for the presence of organisms. INTRODUCTION Culture-proven early onset neonatal infection is confirmed in 10 mg/L), and decision making at 36 h, regarding duration of antibiotic therapy.5 Studies including two systematic reviews of the likelihood ratios for leucocyte indexes and CRP to predict sepsis have all concluded that there is too much heterogeneity within the studies and no such ideal test or combination of tests.29 30 Leucopenia and neutropenia, as well as high immature to total neutrophil ratio (I:T ratio) are undoubtedly associated with increasing odds of infection (ORs 5.38, 6.84 and 7.90, respectively); however, the test sensitivities for detection of sepsis are low.31 The combination of two normal I:T ratios within 24 h and a negative blood culture has been suggested as indicative of a non-infected neonate, and may be a contributory marker to assist with the decision to stop antibiotics.32 Having reviewed the more recent evidence, NICE evidence update advisory group (NICE EUAG) does not recommend full blood count for the diagnosis of EONS as the indices are insufficiently sensitive to exclude EONS6 (box 2).
Serum procalcitonin Procalcitonin (PCT) is the prehormone of calcitonin, normally secreted by thyroid C-cells, and rises within 3–6 h of exposure to infection. It has been suggested that elevated serum PCT concentrations are more sensitive and specific in the differentiation between neonatal infection and inflammation than CRP and may also differentiate between bacterial and viral infection. In a meta-analysis of 16 studies (1959 neonates), the sensitivity and specificity for diagnosing infection were 81% and 79%, respectively.33 Limitations of the evidence included variation in definition of neonatal sepsis, differences in age and gestation of neonates and a high level of statistical heterogeneity among studies analysed. Hence, NICE EUAG concluded that the value of PCT in diagnosis of infection requires further research, and PCT concentration cannot be recommended within the current guideline (box 3).
Cytokine profiles and neutrophil/monocyte adhesion molecules Multiple cytokines, for example, interleukins 6, 8 and 10, and tumour necrosis factor-α, and leucocyte adhesion molecules, for example, CD64, CD11b, have been studied for diagnosis of neonatal sepsis. All lack sufficient sensitivity and specificity to be recommended as diagnostic tools for EONS.14
Antimicrobial therapy Antibiotic therapy drives antibiotic resistance and also alters the types of colonising microbial flora, especially in the gut leading to skewing of immune development. E coli EONS has, at best, remained stable in the USA, but approximately 82% of E coli isolates are resistant to amoxicillin or gentamicin in preterm infants.2 Because gut flora drive the nascent immune system, peripartum antibiotic exposure is increasingly recognised as a
major driver of immune dysregulation, resulting in an increasing incidence of atopy and asthma in childhood.4 Antibiotic therapy should be stopped after 36 h if cultures are negative, if two CRP measurements are negative5 and if there are no further signs of infection. Alternatively, when there is a suspicion that clinical progress is suboptimal, consideration should always be given to an empiric change of antibiotic therapy to include a broader spectrum of pathogens. A multiple logistic regression analysis revealed that empiric treatment failure of EONS could be predicted at 24 h using the following variables: need for vasoactive treatment (OR 2.83 (1.21 to 6.66)); WBC 20 000 per mm3 on day 1 (2.51 (1.09 to 5.81)); I:T ratio >0.2 on day 1 (2.79 (1.10 to 7.11)) and platelet count per 10 000 mm−3 increase on day 1 (0.92 (0.86 to 0.98)).34 Such analyses should be validated in other datasets but have the potential to improve neonatal outcome by ensuring that appropriate antibiotics are used as early as possible. Once a bacterium is identified, the antibiotic regimen should be targeted appropriately. An initial gentamicin dose of 5 mg/kg regardless of gestation has been recommended by NICE CGDG5 but not universally adopted by UK neonatologists, who have concerns regarding renal clearance of gentamicin in very immature babies. If a second dose is required, it is recommended that this should be given at 36 h, with a trough level immediately prior to the second dose, and adjustment of the dose to achieve a trough concentration of
