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Three Part Question

In [neonates presenting with signs of sepsis] is [5 days of IV antibiotic therapy] [adequate treatment]?

Clinical Scenario

A term neonate presents at 24 hours of age with tachyapnoea and a temperature of 37.8 °c following a low-risk normal vaginal delivery. There had been no prolonged rupture of membranes and a high vaginal swab was negative for any significant pathogens. You provisionally diagnose suspected bacterial neonatal sepsis, perform a septic screen, and start IV antibiotics according to local antibiotic protocol. His CRP is 42 and FBC reveals a leukocytosis with left shift on blood film examination. Blood, urine and CSF cultures are all negative. CXR shows no significant focal abnormality. His symptoms resolve over the next few days and you wonder how long antibiotics should be continued.

Search Strategy

MEDLINE 1966 to July 2009; PubMED; EMBASE; British Nursing Index; CAB abstracts; Maternity and Infant Care; CINAHL; and Web of Knowledge. Language restricted to English.
The following terms were used to search electronic databases (duration + antibiot* OR duration + antimicrob*) AND (sepsis OR septic* OR infect*) AND (neonat* OR infant OR newborn OR baby) Limit to English Language
The Cochrane Central Register of Controlled Trials was also searched using the above terms. References from identified studies were examined for possible additional papers.

Search Outcome

14 papers were relevant

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Al-Zwaini E, 2009,	Admissions with suspected sepsis. N= 55. Aged 0- 28 days. >1.5kgs.	Prospective study.	CRP and blood cultures taken at 0 hours; 48 hours; 4/7; 6/7.	Sensitivity (78%); Positive predictive value (86%). CRP should not be used alone. 1:5 female: male neonates. However 50 out of the 55 neonates with suspected sepsis had normal CRP levels by 4 days of treatment (90%).	Based in Iraq-maybe different to UK setting in terms of bacterial flora; hospital setting; and antibiotic susceptibility patterns. CEBM level- 2b. WHO publication.
Carcillo J et al, 2006,	Newborns and children	Expert opinion / review	Opinion	CRP- good predictor in febrile young children. Once paper used was explored -found CRP equally good marker in ill neonates (3-30 days old; n= 20) However less reliable in critically ill children.	Not RCT. CEBM level- 4. Age distribution not stated. Study didn’t look at when CRP normalised. Study in collaboration with Pharmaceutical company. Independent panel review of editors.
Chowdary G. et al, 2006,	Blood culture positive. Randomised after 7 days of age, if symptoms had resolved by 5 days. Statified for birth weight > /= 32/40; >/= 1.5kgs. N= 69. 34 received 7 days IVABs v 35 receiving 14 days.	RCT- Blinded.	Relapse within the first 28 days – with a positive blood culture or clinical signs plus raised CRP.	Treatment failure greater in 7 days group versus 14. Staph Aureus infections had greater failure rates if treated with 7 days. Other infections had equal failure rates regardless of length of treatment. However Staph Aureus babies were more likely to be unwell at 5 days so excluded from RCT.	Small number- 34 v 35. CEBM level 1b- good quality study, but 10% excluded on no consent for trial. Study conducted in India. Maybe different to UK setting in terms of bacterial flora; hospital setting; and antibiotic susceptibility patterns. Population studied had positive blood cultures. No other infection markers were reviewed. Peer reviewed journal.
Ehl S. et al, 1997,	167 newborns, >1.5kgs, with suspected sepsis. Started on antibiotics. CRP was taken @ 24-48 hours- if <10 = Group 1- no infection, and antibiotics were stopped. Those with CRP>10 were randomised into 2 groups. 2A when CRP<10 stopped IVABs. 2B IVABS for 5 days regardless of CRP.	RCT- Prospective.	Relapse with clinical symptoms of infection, within 28 days, requiring antibiotics.	CRP < 10 used as a marker for antibiotic cessation does not increase relapse in first 28 days of life.	Small numbers- 84 v 39 v 43 (1 v 2A v 2B). CEBM Level- 1b Over 2 years- aimed for 50 babies in groups 2A & 2B- not achieved. Study used Mezlocillin and Netilmicin therefore bacterial flora and antibiotic susceptibility patterns reflect that. Don’t show characteristics of groups. Confidence levels not stated. Analysis only on those who stopped IVABs when CRP<10. Those who were clinically unwell and therefore continued IVABs were not included. Symptoms that constituted a relapse were not stated. Mean time to normal CRP in 2A was 3.7 days of IVAB treatment. Peer reviewed journal.
Engle W. et al, 2000,	Those with respiratory distress and CXR changes consistent with pneumonia were recruited. If asymptomatic at >/= 48 hours- randomised to 4 days antibiotics with 24 hour observation post cessation or 7 days.	RCT	Relapse post-discharge.	No blood culture positive babies were found. No relapses occurred in the 4 days IVAB group, and resulted in a shorter hospital stay.	Small numbers- 35 (4 days + obs) v 38 (7 days) CEBM level – 1a. CRP not measured. No organism identified. Study conducted in the USA Hospital protocol of all babies receiving a dose of Penicillin at birth.
Engle W et al, 2003,	Jan-July 2001 >35 gestation, birth weight >2100g Symptom onset>6hrs (to exclude TTN) <24hrs N=26 Randomised at 48 hours of age, only if symptoms had settled, but had demonstratable CXR changes consistent with Pneumonia. CRP measured at 12 and 48 hours. Caesarian section delivery excluded as felt to be high risk of TTN.	RCT	Development of recurrent respiratory symptoms	Duration of 4 days of antibiotics appears to be adequate for term neonates- confirms there previous study. 2 days is inadequate.	Small numbers – 26 in 6 months- ? representative population as spread over that time. Study conducted in USA. Maybe different to UK setting in terms of bacterial flora; hospital setting; and antibiotic susceptibility patterns. Hospital protocol of babies receiving a dose of Penicillin at birth.
Franz A. et al, 2004	Term / preterm infants. <72 hours old. Signs of suspected sepsis, but clinically stable so could wait for the lab results to come back to decide on whether IVAB therapy was required. If IL8>70 and/or CRP >10 randomised to Group A -IVAB treatment until IL8 and CRP normalised. Group B- standard treatment guideline in each study centre . N= 1291. Stratified for gestation.	RCT	Numbers of babies that required a second course of IVABs treatment.	IL8 and CRP group had reduced IVABs However there was an equal reoccurance of the need for subsequent antibiotic therapy compared to conventional therapy.	Included preterm infants. CEBM level- 1b 4 of the 13 blood culture positive babies had a normal CRP. 3 of the 13 blood culture positive had a normal IL8. However all were picked up when the two results were utilised together. 1/5 of mothers received antenatal antibiotics- therefore an unknown clinical impact on study results. Combination of data from 8 centres and 5 countries with differing practice, flora, and organism susceptibility. Peer reviewed journal.
Isaacs D. and Wilkinson A, 1987,	Neonates in the neonatal unit.	Expert opinion	Opinion	If Blood culture negative at 48-72 hours stop IVABx. Proven bacteraemia requires 10 days of antibiotic treatment.	Not a RCT. CEBM level – 5. Validity may be impacted by changing environmental flora; antibiotic usage; organism susceptibility; and population group changes. Population not specified except neonate in neonatal unit. Included early and late onset sepsis. Peer reviewed journal.
Issacs et al, 1987,	Infants prescribed antibiotics for systemic sepsis	Prospective survey 1984-86 Oxford	Mean (SD) duration in days of course	4.25 (4.5) P<0.0001	Peer reviewed journal Blood culture positive study subjects. Validity may be impacted by changing environmental flora; antibiotic usage; organism susceptibility; and population group changes. CEBM level- 1b.
Ng P, 2004,	Newborn infants.	Expert opinion / review	Need test that has high specificity; with good positive value, ideally above 85%.	IL6- early result and sensitive. CRP- late result and specific.	Not RCT. Study conducted in Hong Kong. Maybe different to UK setting in terms of bacterial flora; hospital setting; and antibiotic susceptibility patterns Peer reviewed journal. CEBM level- 5.
Ng P. et al, 2004,	Term babies, with possible early onset sepsis and Pneumonia. <72 hours old. N= 338 babies with suspected sepsis 115 had positive blood cultures v 223 with negative ones. Control was 21 well term babies.	Prospective trial- Blinded	CRP and expression of CD64 on neutrophils at 0 and 24 hours.	Babies with positive cultures had significantly higher CRP and CD64 levels. CD64 in the clinically well is a good enough marker for stopping IVABs at 48 hours. CRP only increased its sensitivity and specificity by a small percentage.	Data collected over 30 months. Appropriate numbers for study. This would not reduce IVABx, as blood culture dictates action ahead of diagnostic markers. CEBM level- 1b Peer reviewed journal.
Nupponen I et al, 2001,	N=39 babies 29-41 weeks GA Suspected sepsis < 48 hours. Positive blood cultures = 22; suspected sepsis = 13; control well term babies= 12.	Retrospective study.	CD116 & IL8 <48 hours of age. Plus CRP.	Markers higher in Sepsis > suspected sepsis > healthy. CRP can be used to stop IVABx when normalised.	Study carried out over 18 months, in two hospitals with only small numbers recruited. Study based in Finland. Maybe different to UK setting in terms of bacterial flora; hospital setting; and antibiotic susceptibility patterns. Controls were well term babies when the study included 29-41 GA babies- possible bias to results, as populations differ. Peer reviewed journal. CEBM level- 2b.
Philip A & Mills P, 2000,	1997-98 >1.5kg CRP was taken at birth and at 12 hours of age. If abnormal results obtained, a further CRP was taken 12 hours later with a blood culture and IVABx started. No central venous access No Respiratory Support Excluded if CRP<10 N= 425.	Randomized-Controlled Trial	A return to a normal CRP was used to discontinue IVABx. Relapse requiring second course of antibiotics in the first 4 weeks of life was used to access its predictive value.	CRP <10 is an effective marker for discontinuing antibiotics.	Blinding not stated Babies treated with Ampicillin and Gentamicin therefore different organisms and organism sensitivity maybe evident. Single centre in Germany, but good study numbers recruited. Includes GBS. Includes preterm infants. Peer reviewed journal. CEBM level - 1b Mean length of CRP guided IVABx was 3.1 days.
Spitzer et al, 2005,	Term infants, >2.5Kg, asymptomatic by 24 hours of life, with no signs of respiratory distress and receiving oral feeds. Negative blood cultures	Retrospective analysis of large neonatal database (2001-2002) USA	Duration of antibiotic therapy	Infants treated for mean 3.29 days +/- 1.8 (SD) (range 1-10 days) with no maternal risk factors. Length of antibiotic therapy was not influenced by presence or absence of maternal risk factors for sepsis.	Did not record WCC or CRP. Peer reviewed journal. CEBM level- 2b. This was a correlation of data only to demonstrate varying practice in antibiotic therapy across the hospitals who utilise the USA neonatal database.

Comment(s)

Infection is an important cause of neonatal mortality and morbidity. Clinical features are often non-specific and a high index of suspicion is required by the clinician. In bacterial neonatal sepsis there is some guidance with regard to optimal duration of therapy for specific micro-organisms. GBS sepsis is treated with 10 days IV antibiotics, GBS meningitis for 14 -21 days, and E Coli for 14 days (Isaacs and Wilkinson, 1987; Isaacs and Moxon, 1999; Madappa and Go, 2009). Blood culture is the gold standard for diagnosis but culture reports are only available after 48 hours, and several of the above papers suggest that a negative result can be falsely reassuring. Incorrect sampling may dilute organism collection; previous maternal antibiotic therapy may impact on culture; or the organisms may be slow-growing or unculturable (Forward, 2006).

Decisions regarding length of antibiotic therapy can be difficult as there is often limited data. Inadequate antibiotic therapy may lead to recurrence of symptoms and complications. Too long duration also has drawbacks including bacterial resistance, increased costs, effects on maternal infant bonding, and nosocomial infection. As only a small proportion of infants will have positive blood cultures (<10%), it is important to find out what the most appropriate duration of antibiotics is. There is significant variation in practice with no definitive guidelines. The aim of this review was to review the current evidence for length of antibiotic therapy in this group of infants.

There is no good quality studies that specifically address the question posed, that is the length of antibiotic therapy in the term neonate with suspected sepsis; negative cultures, but with a CRP rise. The two papers in Table 1 are closest to the question population, but fail to provide answers due to methodological deficits and differing approaches to the research question. In order to better address the question posed here the population specifics were widened to encompass premature infants; positive blood cultures; CXR changes; and differing infection markers. The resulting papers are displayed in Table 2. Even this more diffuse search failed to produce clarity in respect to appropriate antibiotic therapy for suspected early onset neonatal sepsis.

Editor Comment

CEBM Centre for Evidence Based Medicine; CRP C-Reactive protein; CXR chest x-ray; E-coli Escherichia coli; VABx intravenous antibiotic treatment; GA gestational age; GBS Group B Streptococcus; IL8 Interleukin 8; RCT randomised control trial;WCC white cell count.

Clinical Bottom Line

1. No changes to practice can be recommended on the basis of this review.

2. CRP and other inflammatory markers may guide future practice in this area more definitively. Several of the above papers used CRP to discontinue IVABx in conjunction with clinical condition. They state that using this guidance, IVABx was reduced to an average of 3.1- 3.8 days without increase in relapse rates. Even if IVABx treatment was reduced to 4 days rather than the standard practice of at least 5 days, the advantage globally would be enormous. This would reduce resistance rates, shorten hospital admission, reduce parental anxiety, reduce the need for recannulation, reduce the risk of extravastation injury/secondary infection, decrease workload, and result in savings of £189-355 per day (O'Neill et al, 2000).

3. In view of the potential benefits of shortened duration of antibiotic therapy in the group of newborns under question, it is imperative that future research be targeted in this field, for example in the use of infection panels such as IL8, CRP, and Procalcitonin.

References

1. Al-Zwaini E. C-Reactive Protein: A useful marker for guiding duration of antibiotic therapy in suspected neonatal septicaemia. Eastern Mediterranean Health Journal. 2009 15 (2): pp 269- 275.
2. Carcillo J et al. Early markers of infection and sepsis in newborns and children. Advances in Sepsis 2006 5(4): pp 118- 125.
3. Chowdary G. et al. Randomised Controlled trial of 7-day vs 14-day antibiotics for neonatal sepsis. Journal of Tropical Pediatrics. 2006 52 (6): pp 427-432.
4. Ehl S. et al C-Reactive Protein is a useful marker for guiding duration of antibiotic therapy in suspected neonatal bacterial infectio. Pediatrics. 1997 99: pp 216-221.
5. Engle W. et al Neonatal pneumonia: Comparison of 4 vs 7 days of antibiotic therapy in term and near term infants. Journal of Perinatology. . 2000 20 (7): pp 421-426.
6. Engle W et al. Pneumonia in Term Neonates: Laboratory Studies and duration of Antibiotic Therapy. Journal of Perinatology. 2003 23: pp 372-377.
7. Forward K. An evaluation of extended incubation time with blind subculture of blood cultures in patients with suspect endocarditis. The Canadian Journal of Infectious Diseases and Medical Microbiology. 2006 17 (3): pp 186-188.
8. Franz A. et al. Measurement of Interleukin 8 in combination with C-Reactive Protein reduced unnecessary antibiotic therapy in newborn infants: A multicenter, randomised controlled trial. Pediatrics 2004 114 (1): pp 1-8.
9. Isaacs D. and Moxon R. Handbook of Neonatal Infections: A practical guide. London: WB Saunders 1999
10. Isaacs D. and Wilkinson A. Antibiotic use in the Neonatal Unit. Archives of Disease in Childhood. 1987 62: pp 204-208.
11. Isaacs D, Wilkinson AR, and Moxon ER. Duration of antibiotic course for neonates. Archives of Disease in Childhood. 1987 62: pp 727-728.
12. Madappa T. and Go C. Escherichia Coli Infections. (Accessed 01 March 2010). http://emedicine.medscape.com/article/217485-overview 2009
13. Ng P. Diagnostic markers of infection in neonates. Archives of Disease in Childhood.Fetal and Neonatal edition. 2004 . 89: F229-235.
14. Ng P. et al. Neutrophil CD64 is a sensitive diagnostic marker for early-onset neonatal infection. Ped Res 2004 56(5): pp 796- 803.
15. Nupponen I et al. Neutrophil CD11b expression and circulating Interleukin-8 as diagnostic markers for early-onset neonatal sepsis. Pediatrics 2001108(1): pp e12.
16. O'Neill C. et al A cost analysis of neonatal care in the UK: Results from a multicentre study. Journal of Public Health Medicine. 2000 22(1): pp 108-115.
17. Philip A and Mills P. Use of C-Reactive Protein in minimizing antibiotic exposure: Experience with infants initially admitted to a well-baby nursery. Pediatrics 2000 106(1): pp e4.
18. Spitzer A, Kirkby S, and Kornhauser M. Practice variation in suspected neonatal sepsis: A costly problem in neonatal intensive care. Journal of Perinatology. 2005 25(4): pp 265-269.