Antibiotic guidelines for the neonatal unit

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⁾ 

• 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

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.
• Listeria – IV 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.

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.

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 sepsis.  Metronidazole 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.  

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

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

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.