Antibiotic guidelines for the neonatal unit

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Objectives

This guideline is applicable to all medical, nursing and midwifery staff working with neonates in West of Scotland.  Prevention of sepsis is important and all staff should be familiar with other guidelines relating to hand hygiene and aseptic technique.  Staff should also refer to West of Scotland Neonatal MCN guideline for Early Onset Sepsis in the Neonate, and to the relevant pharmacy monographs for medications referred to in this guideline.  It is important to remember to liaise closely with microbiology and infection control departments.

Background
  • Good infection control practice is of paramount importance in reducing the spread of infection. Always clean your hands before and after each patient contact.  Alcohol gel is effective, although if hands are visibly soiled please use soap and water
  • The epidemiology of neonatal sepsis varies geographically and is constantly changing, with secular trends being interrupted by outbreaks and epidemics.
  • Sepsis in neonates can be rapidly aggressive, and is associated with later complications. (1)(2)
  • Liaison with a microbiologist familiar with neonatal practice is recommended for atypical organisms or poor clinical response.
  • In some parts of the world antibiotic resistance is widespread among the commonest organisms seen infecting neonates.(3)(4)(5)(6-8)(9) This is likely to be a result of national as well as local antibiotic prescribing patterns.
  • Given that the Cochrane systematic reviews found only 2 small studies comparing different antibiotic regimens in early onset sepsis, and only 1 small study in late onset sepsis, clearly there is a need for more evidence on which to base guidelines such as this one.(10)(11)(12)
  • Infection control is crucial for prevention of nosocomial infection, and policies on breast milk feeding and venous catheters will also impact on infection rates.(13)(14)(15)(16)
  • The long term consequences of abnormal gut colonization due to antibiotic pressure, which can be persistent, are unclear.(17)
Intrapartum prophylaxis

Group B Streptococcus – see the West of Scotland Early onset Sepsis guideline.

Streptococcus pneumoniae - Maternal vaginal colonization with S. pneumoniae is rare (0.11%), but associated with a high risk of infection in the newborn.   Intrapartum prophylaxis with benzylpenicillin as per Group B Streptococcus should be considered.(18) 

 

Investigation of a baby suspected of neonatal sepsis
  • FBC
  • CRP
  • Coagulation – only if low platelets or abnormal bruising suggestive of disseminated intravascular coagulation
  • Blood culture
    • Cultures should be taken prior to the commencement of antibiotic therapy
    • At least 0.5ml should be taken.(19, 20) and ideally 1ml.(21) Bigger samples are more sensitive and are also associated with lower contamination rates.(22)  A single sample of at least 1ml is virtually as good as multiple samples (23)
    • If colonization of a surgically implanted central venous line is strongly suspected, a separate sample may be taken from the central line in addition to the peripheral sample.  (This is not usually possible or necessary for PICC Lines).
  • Urine culture - If a urinary source for sepsis is suspected (late onset sepsis only), urine should be obtained by suprapubic aspiration. Request microscopy if concern about fungal sepsis.
  • Lumbar puncture - not necessary for asymptomatic babies with obstetric risk factors for sepsis, or early respiratory distress syndrome alone. It is particularly relevant where gram negative or fungal sepsis is suspected.(25)
  • Swabs
    • If a surgically placed central line is present, swabs from the exit site may be helpful, if inflammation is present, as they may predict catheter related infection.(26) It is not required to swab the entry site of a PICC line as removal of the dressing risks dislodgement or contamination of the line.
    • Surface swabs if infected skin lesion
    • Placental swab if chorioamnionitis
  • Viral tests – Appropriate to presenting features - see WoS Guideline for Virological assessment of neonates
Early onset sepsis

Definition – Infection presenting within the first 72 hours of life.  Infecting organism acquired antenatally or intrapartum.  May be associated with chorioamnionitis.

Epidemiology

The commonest organisms are from the vaginal flora

  • Group B Streptococcus – incidence may be modified by Intrapartum Prophylaxis
  • Gram negative rods

Less commonly seen

  • Staphylococci
  • Streptococci – pneumococci, enterococci
  • Haemophilus
  • Listeria

Empiric therapy

  • IV Benzylpenicillin and Gentamicin

Cefotaxime should be avoided on the neonatal unit for empirical therapy.  It is associated with increased rates of colonization with strains resistant to the empirical therapy, with higher rates of Extended Spectrum Beta Lactamase (ESBL) infections, invasive candidiasis and death.(27)(28)(29).  However it should be considered in infants with meningitis –see below

Other conditions to consider

  • Bacterial meningitis – IV Cefotaxime and Gentamicin
    If clinical findings are strongly suggestive of meningitis or where CSF analysis demonstrates a leucocytosis or where organisms are found on Gram stain or CSF culture, Cefotaxime should be used instead of Benzylpenicillin
    NB - The possibility of meningitis should be considered in those infants with positive cultures for Group B Streptococcus, Gram-negative organisms or Listeria as this will influence the type and length of therapy.
  • ListeriaIV Amoxicillin and Gentamicin
    Listeriosis should be considered in the septicaemic or meningitic preterm infant born to a febrile mother with frank chorioamnionitis. A granulomatous skin rash in the newborn would be another indicator.
  • Congenital Cytomegalovirus (CMV) or Herpes Simple Virus (HSV) infection if any of the following are present - see HSV & CMV guidelines for management:
  • Petechial or vesicular rash
  • Thrombocytopenia or coagulopathy
  • Hepatomegaly or hepatitis
  • Meningitis/encephalitis

Rationalization

Once an organism has been isolated, the antibiotic should be rationalized to the narrowest spectrum that effectively covers the organism in the site it has been isolated from.  See below for specific organisms. 

Duration - Consider stopping antibiotics:-

  • Where symptoms have resolved - After 2 normal CRP samples at least 12 hours apart. 
  • Where symptoms persist – After 2 normal CRP samples at least 12 hours apart and blood culture is negative – Consider non-microbiological  cause of the symptoms (30)(31)
  • After at least 7 days for positive blood culture with septicaemia as guided by organism (see below), clinical response and CRP

Consider repeat cultures and utilizing antibiotics for late-onset sepsis if there are ongoing signs/symptoms or rising CRP despite 24-48 hours of treatment.

Late onset sepsis

Definition: Infection presenting after 72 hours of life.  Includes nosocomial infections and translocation of organisms across the immature gut wall.  Associated with indwelling lines, catheters, ET tubes and drains

Epidemiology - The commonest organisms

  • Coagulase negative staphylococci – St. Epidermidis
  • Coagulase positive staphylococci – St. Aureus
  • Gram negative rods
  • Candida

Empiric Therapy

  • IV Vancomycin and Gentamicin

Other conditions to consider

  • Bacterial meningitis – Add IV Cefotaxime
    If clinical findings suggestive – see below. The possibility of meningitis should be considered in those infants with cultures positive for Gram-negative organisms as this will influence the type and length of therapy. 
  • Fulminant or Gram -ve sepsis unresponsive to empiric therapy.
    Add Piperacillin/Tazobactam (Tazocin)

    Meropenem may be considered as an alternative to Piperacillin / Tazobactam (Tazocin) but should be reserved for circumstances of proven resistance or where local epidemiology indicates high risk of resistance. 
  • Viral Infection – If symptoms & signs are suggestive of meningitis / encephalitis without evidence of bacterial infection on CSF microscopy OR If signs & symptoms of generalized sepsis persist despite antibiotic therapy and blood cultures remain negative - Consider Aciclovir. For more details please see MCN guidelines for HSV infection and for Virological investigations in the neonate
  • Candidal infection – Add IV Ambisome - (see section below for fungal prophylaxis)
    If Cultures are positive for fungal infection or where signs or symptoms of sepsis persist despite appropriate antibiotic therapy as outlined above. (In these circumstances, discuss with microbiology).

    Other features which may indicate a risk of fungal infection include:-
    • VLBW babies
    • Thrombocytopaenia
    • Babies who have been on broad-spectrum or prolonged antibiotic courses.
    • Where there is known to be candidal colonization of multiple sites or central line sites  (32)(33)

Rationalization

Once an organism has been isolated (assuming it is not considered a contaminant), rationalize the antibiotic regimen to the narrowest spectrum that effectively covers the organism in the site from which it has been isolated.  See below for specific organisms. 

Duration - Consider stopping antibiotics:-

  • Where symptoms have resolved - After 2 normal CRP samples at least 12 hours apart. 
  • Where symptoms persist – After 2 normal CRP samples at least 12 hours apart and blood culture is negative – Consider non-microbiological  cause of the symptoms (30)(31)
  • After at least 5 days for positive blood culture with septicaemia as guided by organism (see below), clinical response and CRP

Consider repeat cultures if there are ongoing signs/symptoms or rising CRP despite 24-48 hours of treatment.  Central venous lines may need to be removed in Candidal infection or in Staphylococcal infections which do not respond to therapy

Duration of treatment

Consider stopping antibiotics after a minimum of:  

  • At 5 days for Coagulase negative Staphylococci (CoNS) sepsis
  • At 7 days for non-CoNS septicaemia (but see also specific clinical situations below)
  • At 14 days for Staph. aureus septicaemia (see below)
  • At 14 days for Group B Streptococcal meningitis
  • At 21 days for Gram-negative meningitis
  • At 21 days for Listeria meningitis

see Table 1 for more detail [Adjuncts section below]

The decision to stop antibiotics should be guided by clinical response and serial CRP.  If persisting symptoms/signs or abnormal CRP, consider:

  • Repeating cultures (including urine, LP)
  • Optimizing antibiotic doses and levels
  • Further investigations (e.g. echo, X-ray, ultrasound) to look for a focus
  • Changing to an alternative antibiotic e.g. Piperacillin/ Tazobactam (Tazocin) / Meropenem*
  • Adding Ambisome - blood cultures are often negative in fungal sepsis or only positive after 48 hours.  Abdominal and cranial ultrasound, echo and ophthalmology review may reveal the presence of mycetomas.
Specific Clinical Situations

Meningitis

Suspected: use Cefotaxime and Gentamicin in early onset sepsis, Cefotaxime and Vancomycin for late onset sepsis pending culture and microscopy results.

Gram positive: use Cefotaxime
Cephalosporin resistance is rare and microbiological advice should be sought in such cases.  Avoid vancomycin monotherapy as CSF penetration is variable (7–68%).(35)

Gram negative: use Cefotaxime and Gentamicin

The adjunctive use of aminoglycosides for meningitis is controversial - CSF penetration in adults is poor, although it has not been studied in neonates.  Nonetheless, clinical studies show efficacy with “once-daily” dosing.(35) 1 centre has reported excellent outcomes with combination treatment for gram negative meningitis in neonates (uncontrolled).(36)

N.B. If an Extended Spectrum Beta Lactamase organism is identified, discuss alternative antibiotics with consultant microbiologist.   

Avoid intraventricular antibiotics.(37)

NEC

Use the standard combination as for late onset sepsisMetronidazole is usually added on the advice of our surgical colleagues where NEC is confirmed or where perforation has been demonstrated radiologically although those infants who are already on Tazocin or Meropenem should have sufficient anaerobic cover.

Extended-Spectrum Beta-Lactamase (EBSL) organisms

Discuss alternative antibiotic regimen with consultant microbiologist

The emergence of extended spectrum beta lacatamase resistance has been associated with increased use of broad spectrum cephalosporins.  Outbreaks of multiresistant Klebsiella and Enterobacter have been described in neonatal units.(38)(39)  Mortality with such strains appears to be worse, not least due to the delay in initiating effective antibiotics pending laboratory identification.(8)(40)

Remember infection control measures.  Pending surveillance cultures, consider temporarily amending the unit antibiotic policy regimen for late onset sepsis to include 1 antibiotic effective against the identified ESBL.(14)  Such a move would require discussion with microbiology and IPC via appropriate governance mechanism.

Listeria

Use Amoxicillin plus Gentamicin

 Although this is the most effective antibiotic regimen for listeriosis, the cure rate is only approximately 70%.  These antibiotics only poorly penetrate the cerebrospinal fluid and thus high doses given over a prolonged period of 2-3 weeks are necessary.  In difficult cases Quinolones (Ciprofloxacin) may have a role.(41) 

Meconium staining of the amniotic fluid does not appear to be a useful indicator of Listeriosis where the incidence of infection is very low.(42)   It may be more useful to assess avoidance of soft blue or mould ripened cheeses and paté during pregnancy.

Staphylococcus aureus

Use Flucloxacillin (except MRSA).  

Standard treatment duration for septicaemia is 2 weeks.  If good clinical response, oral flucloxacillin could be used for the second week with careful  monitoring  For relapsing/persisting infections, look for, osteomyelitis,  abscesses or infected thrombus e.g. IV sites, deep veins, heart.  Abscesses may require drainage.  Deep vein thrombophlebitis, osteomyelitis or endocarditis require an extended treatment course e.g. 4-6 weeks.  Adjunctive treatment with Rifampicin or Fusidic acid should also be considered. 

MRSA

Use Vancomycin

Rifampicin or Fusidic acid may be useful for difficult cases.   

Linezolid has been used successfully in cases unresponsive to all other antibiotic regimens.  However, this antibiotic is poorly studied in neonates and should only be used in consultation with microbiology and after discussion with parents   See also Staphylococcus aureus, above.   

Acinetobacter and Stenotrophomonas -  Discuss with Consultant Microbiologist

These infections are often multiresistant, and even where sensitive may not respond well to treatment.  Any central lines should be removed immediately.  Ciprofloxacin* has been used for Acinetobacter with some benefit in unresponsive cases.(43)

Candida

          Anti- Fungal Prophylaxis

  • Dependant on local candida infection rates it may be appropriate to consider anti-fungal prophylaxis, with Fluconazole, for high-risk infants. This may include babies who are very low birth weight and who have been on broad-spectrum or prolonged antibiotic regimens. Also where there is known colonization at multiple sites, or at a central line site.(32)(33).

The decision to use anti-fungal prophylaxis will be made on an individual unit basis informed by local monitoring of infection rates.

Candidal Infection

Empiric therapy for suspected candidal sepsis or where Candida isolated from culture is with Ambisome (liposomal Amphoteracin).  Fluconazole is also effective against most Candida species and may be used as an alternative therapy following determination of sensitivity. 
Once a fungal septicaemia has been identified, remove any central lines immediately as a failure to do so increases mortality and morbidity.(33)(44)
For resistant Candida or poor response to treatment, seek microbiological advice.  Consider adjuvant treatment for immunodeficiency and surgery for large lesions.  

Adjuncts

Given that variations will be seen in factors such as protein binding and antibiotic sensitivity, before other adjuncts are considered always ensure that good doses of the appropriate antibiotics are being used, with good levels where measurable.

G/GM-CSF – no overall benefit is demonstrated for adjunctive or prophylactic use.(45)(46)(47)

Intravenous immunoglobulin  - A large multi-center study of Intravenous immunoglobulin therapy for the treatment of neonatal sepsis (INIS) has found no benefit for the treatment of neonatal sepsis ((48) full publication awaited).  This therapy is not indicated unless there is known to be a congenital deficiency of immunoglobulin production   

Table 1 - Common Organisms and Recommended Antibiotics

Gram stain

Organism

1st line antibiotic

Adjunctive Antibiotic

2nd line antibiotic

Duration of treatment for sepsis – Add 7d for meningitis

Gram positive (cocci)

Group B streptococcus

Benzylpenicillin

Gentamicin

 

7 days

Staph aureus

Flucloxacillin

 

Rifampicin, Fucidin

14 days

MRSA

Vancomycin

Fucidin, Rifampicin, depending on sensitivities

Linezolid

14 days

Staph epid (coag neg)

Vancomycin

 

Rifampicin, Fucidin

5 days

Enterococcus faecalis

Amoxicillin

 

Vancomycin

7 days

Gram positive (bacilli)

Listeria

Amoxicillin 

Gentamicin

 

14 days

Gram negative (bacilli)

E. coli, Klebsiella, Enterobacter

Gentamicin

Piperacillin/ Tazobactam (Tazocin), Meropenem dependent on local microbiological advice

 

7 days

Fungal

Candida

Ambisome

 

Fluconazole

14 Days

 

* as guided by clinical response, blood cultures, and serial CRP. 

 


Algorithm

Gram Stain

Organism

1st Line Antibiotic

Adjunctive Antibiotic

2nd Line Antibiotics
Guided by Sensitivities when available and discussion with microbiology

Gram Positive cocci

Β-Haemolytic Strep. Pneumococcus

Penicillin

Gentamicin

 

Staph Aureus

Flucloxacillin

 

Fucidin, Rifampicin

MRSA

Vancomycin

Fucidin, Rifampicin, depending on sensitivities

Linezolid

Coagulase negative Staph.

eg. Staph Epidermidis

Vancomycin

 

Fucidin, Rifampicin

Enterococcus faecalis

Amoxicillin

 

Vancomycin

Gram positive bacilli

Listeria

Amoxicillin

Gentamicin

 

Gram negative Bacilli

Coliforms, Pseudomonas

Gentamicin

Tazocin

Meropenem

Audit questions

Audit Questions - Suggestions

  • Audit of local epidemiology
    • Incidence of Early Onset Sepsis broken down by
      • Site
      • Organism
      • Resistant strains
    • Incidence of Late onset sepsis
      • Organism
      • Resistant strains
      • Line related sepsis

Duration of antibiotic therapy in infants without CRP rise and without positive culture.

References
  1. 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. J Pediatr. 1996 Jul;129(1):72-80.
  2. Stoll BJ, Hansen N. Infections in VLBW infants: Studies from the NICHD neonatal research network. Semin Perinatol. 2003 Aug;27(4):293-301.
  3. Lee NC, Chen SJ, Tang RB, Hwang BT. Neonatal bacteremia in a neonatal intensive care unit: Analysis of causative organisms and antimicrobial susceptibility. JCMA. 2004;67(1):15--20.
  4. Espino Hernandez M, Couto Ramos MJ, Fiol Ferrer N, Rojas Hernandez N. [Resistance to antimicrobials and combination therapy assessment in neonatal sepsis]. [spanish]
    Pan American Journal of Public Health. 2003;13(4):214-21.
  5. Mammina C, Di Carlo P, Cipolla D, Giuffre M, Casuccio A, Di Gaetano V, et al. Surveillance of multidrug-resistant gram-negative bacilli in a neonatal intensive care unit: Prominent role of cross transmission. American Journal of Infection Control. 2007;35(4):222.
  6. Waheed M, Laeeq A, Maqbool S. The etiology of neonatal sepsis and patterns of antibiotic resistance. Jcpsp, Journal of the College of Physicians & Surgeons - Pakistan. 2003 Aug;13(8):449-52.
  7. Tallur SS, Kasturi AV, Nadgir SD, Krishna BV. Clinico-bacteriological study of neonatal septicemia in hubli. Indian J Pediatr. 2000 Mar;67(3):169-74.
  8. Sehgal R, Gaind R, Chellani H, Agarwal P. Extended-spectrum beta lactamase-producing gram-negative bacteria: Clinical profile and outcome in a neonatal intensive care unit. Ann Trop Paediatr. 2007 Mar;27(1):45-54.
  9. Desinor OY, Silva JL, Menos MJ. Neonatal sepsis and meningitis in haiti. J Trop Pediatr. 2004 Feb;50(1):48-50.
  10. Mtitimila EI, Cooke RW. Antibiotic regimens for suspected early neonatal sepsis. Cochrane Database of Systematic Reviews. 2004(4):004495.
  11. Gordon A, Jeffery HE. Antibiotic regimens for suspected late onset sepsis in newborn infants. The Cochrane database of systematic reviews. 2005(3):CD004501.
  12. Lopez Sastre JB, Fernandez Colomer B, Coto Cotallo GD, Ramos Aparicio A, Grupo de Hospitales C. Trends in the epidemiology of neonatal sepsis of vertical transmission in the era of group B streptococcal prevention. Acta Paediatrica. 2005 Apr;94(4):451-7.
  13. Bass S, Hawkey PM, Fraise AP, Cunningham BA, Tillotson GS, Gill MJ. A long-term ecological study of two defined empirical antibiotic regimens in intensive care units. Infectious Diseases in Clinical Practice. 2006.;14(5):273-80.
  14. van der Zwet WC, Parlevliet GA, Savelkoul PH, Stoof J, Kaiser AM, Koeleman JG, et al. Nosocomial outbreak of gentamicin-resistant klebsiella pneumoniae in a neonatal intensive care unit controlled by a change in antibiotic policy. J Hosp Infect. 1999 Aug;42(4):295-302.
  15. Clark R, Powers R, White R, Bloom B, Sanchez P, Benjamin DK,Jr. Prevention and treatment of nosocomial sepsis in the NICU. Journal of Perinatology. 2004 Jul;24(7):446-53.
  16. Kilbride HW, Wirtschafter DD, Powers RJ, Sheehan MB. Implementation of evidence-based potentially better practices to decrease nosocomial infections. Pediatrics. 2003;111(4 Pt 2):e519.
  17. Bedford Russell AR, Murch SH. Could peripartum antibiotics have delayed health consequences for the infant? BJOG: An International Journal of Obstetrics & Gynaecology. 2006 Jul;113(7):758-65.
  18. Marcus KA, Verduin CM, Halbertsma FJ. [Invasive pneumococcal infection in 5 newborns, 1996-2004]. Ned Tijdschr Geneeskd. 2007 Nov 10;151(45):2527-30.
  19. Brown DR, Cohen M, Chan T, Rai B, Kutler D. Bacterial concentration and blood volume required for a positive blood culture. Journal of Perinatology. 1995;15(2):157.
  20. Connell T, Rele M, Cowley D, Buttery J, Curtis N. How reliable is a negative blood culture result? volume of blood submitted for culture in routine practice in a children's hospital. Pediatrics. 2007;119(5):891.
  21. Schelonka RL, Chai MK, Yoder BA, Hensley D, Brockett RM, Ascher D. Volume of blood required to detect common neonatal pathogens. J Pediatr. 1996;129(2):275.
  22. Bekeris LG, Tworek JA, Walsh MK, Valenstein PN. Trends in blood culture contamination: A college of american pathologists Q-tracks study of 356 institutions. Archives of Pathology Laboratory Medicine. 2005;129(10):1222.
  23. Sarkar S, Bhagat I, DeCristofaro JD, Wiswell TE, Spitzer AR. A study of the role of multiple site blood cultures in the evaluation of neonatal sepsis. Journal of Perinatology. 2006 Jan 1;26(1):18-22.
  24. Guerti K, Ieven M, Mahieu L. Diagnosis of catheter-related bloodstream infection in neonates: A study on the value of differential time to positivity of paired blood cultures. Pediatric critical care medicine. 2007;8(5):470.
  25. Eldadah M, Frenkel LD, Hiatt IM, Hegyi T. Evaluation of routine lumbar punctures in newborn infants with respiratory distress syndrome. Pediatr Infect Dis J. 1987;6(3):243.
  26. Mahieu LM, De Muynck AO, Ieven MM, De Dooy JJ, Goossens HJ, Van Reempts PJ. Risk factors for central vascular catheter-associated bloodstream infections among patients in a neonatal intensive care unit. J Hosp Infect. 2001;48(2):108.
  27. Quinn JP, Rodvold KA. Antibiotic policies in neonatal intensive-care units. Lancet. 2000 Mar 18;355(9208):946-7.
  28. Le J, Nguyen T, Okamoto M, McKamy S, Lieberman JM. Impact of empiric antibiotic use on development of infections caused by extended-spectrum beta-lactamase bacteria in a neonatal intensive care unit. Pediatr Infect Dis J. 2008 Apr;27(4):314-8.
  29. Clark RH, Bloom BT, Spitzer AR, Gerstmann DR. Empiric use of ampicillin and cefotaxime, compared with ampicillin and gentamicin, for neonates at risk for sepsis is associated with an increased risk of neonatal death. Pediatrics. 2006 Jan;117(1):67-74.
  30. Benitz WE, Han MY, Madan A, Ramachandra P. Serial serum C-reactive protein levels in the diagnosis of neonatal infection. Pediatrics. 1998;102(4):E41.
  31. Mathai E, Christopher U, Mathai M, Jana AK, Rose D, Bergstrom S. Is C-reactive protein level useful in differentiating infected from uninfected neonates among those at risk of infection?. Indian Pediatr. 2004 Sep;41(9):895-900.
  32. Uko S, Soghier LM, Vega M, Marsh J, Reinersman GT, Herring L, et al. Targeted short-term fluconazole prophylaxis among very low birth weight and extremely low birth weight infants. Pediatrics. 2006;117(4):1243.
  33. Manzoni P, Farina D, Leonessa M, d'Oulx EA, Galletto P, Mostert M, et al. Risk factors for progression to invasive fungal infection in preterm neonates with fungal colonization. Pediatrics. 2006 Dec;118(6):2359-64.
  34. Ng PC, Cheng SH, Chui KM, Fok TF, Wong MY, Wong W, et al. Diagnosis of late onset neonatal sepsis with cytokines, adhesion molecule, and C-reactive protein in preterm very low birthweight infants. Archives of disease in childhood. Fetal and neonatal edition. 1997;77(3):F221.
  35. de Hoog M, Mouton JW, van den Anker JN. New dosing strategies for antibacterial agents in the neonate. Seminars In Fetal & Neonatal Medicine. 2005 Apr;10(2):185-94.
  36. Dellagrammaticas HD, Christodoulou C, Megaloyanni E, Papadimitriou M, Kapetanakis J, Kourakis G. Treatment of gram-negative bacterial meningitis in term neonates with third generation cephalosporins plus amikacin. Biol Neonate. 2000 Mar;77(3):139-46.
  37. Shah S, Ohlsson A, Shah V. Intraventricular antibiotics for bacterial meningitis in neonates. Cochrane Database of Systematic Reviews. 2004(4):004496.
  38. Royle J, Halasz S, Eagles G, Gilbert G, Dalton D, Jelfs P, et al. Outbreak of extended spectrum beta lactamase producing klebsiella pneumoniae in a neonatal unit. Archives of Disease in Childhood Fetal & Neonatal Edition. 1999 Jan;80(1):F64-8.
  39. Modi N, Damjanovic V, Cooke RW. Outbreak of cephalosporin resistant enterobacter cloacae infection in a neonatal intensive care unit. Arch Dis Child. 1987 Feb;62(2):148-51.;62(2):148--151.
  40. Chiu S, Huang YC, Lien RI, Chou YH, Lin TY. Clinical features of nosocomial infections by extended-spectrum beta-lactamase-producing enterobacteriaceae in neonatal intensive care units. Acta Paediatrica. 2005 Nov;94(11):1644-9.
  41. Hof H. An update on the medical management of listeriosis. Expert Opin Pharmacother. 2004 Aug;5(8):1727-35.
  42. Tybulewicz AT, Clegg SK, Fonfe GJ, Stenson BJ. Preterm meconium staining of the amniotic fluid: Associated findings and risk of adverse clinical outcome. Archives of Disease in Childhood Fetal & Neonatal Edition. 2004 Jul;89(4):F328-30.
  43. Mishra A, Mishra S, Jaganath G, Mittal RK, Gupta PK, Patra DP. Acinetobacter sepsis in newborns. Indian Pediatr. 1998 Jan;35(1):27-32.
  44. Benjamin DK,Jr, Ross K, McKinney RE,Jr, Benjamin DK, Auten R, Fisher RG. When to suspect fungal infection in neonates: A clinical comparison of candida albicans and candida parapsilosis fungemia with coagulase-negative staphylococcal bacteremia. Pediatrics. 2000 Oct;106(4):712-8.
  45. Carr R, Modi N, Dore C. G-CSF and GM-CSF for treating or preventing neonatal infections. Cochrane Database of Systematic Reviews. 2003(3):003066.
  46. Bilgin K, Yaramis A, Haspolat K, Tas MA, Gunbey S, Derman O. A randomized trial of granulocyte-macrophage colony-stimulating factor in neonates with sepsis and neutropenia. Pediatrics. 2001 Jan;107(1):36-41.
  47. Carr R, Brocklehurst P, Doré CJ, Modi N. Granulocyte-macrophage colony stimulating factor administered as prophylaxis for reduction of sepsis in extremely preterm, small for gestational age neonates (the PROGRAMS trial): A single-blind, multicentre, randomised controlled trial. Lancet. 2009;373(9659):226.
  48. The INIS Collaborative Group. Treatment of Neonatal Sepsis with Intravenous Immune Globulin N Engl J Med 2011;365:1201-11.
Editorial Information

Last reviewed: 19 April 2018

Next review: 01 April 2021

Author(s): Dr Andrew Powls – Consultant Paediatrician PRM

Co-Author(s): Other Professionals Consulted: Dr Brian Jones – Consultant Microbiologist GG&C; Fiona Anderson – Pharmacist PRM

Approved By: WoS Neonatal MCN