Invasive Candidiasis in Neonates - Guideline for the Management of

Publication: 01/03/2009  --
Last review: 13/07/2018  
Next review: 13/07/2021  
Clinical Guideline
CURRENT 
ID: 305 
Approved By: Improving Antimicrobial Prescribing Group 
Copyright© Leeds Teaching Hospitals NHS Trust 2018  

 

This Clinical Guideline is intended for use by healthcare professionals within Leeds unless otherwise stated.
For healthcare professionals in other trusts, please ensure that you consult relevant local and national guidance.

Guideline for the Management of Invasive Candidiasis

Summary
Invasive Candidiasis in Neonates

Diagnostic criteria
Criteria for use of guidelines

  • Neonatal patients either at risk of or diagnosed with invasive candidiasis in neonates

Investigations
See main guidelines

Treatment
See main guidelines

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Background

Invasive fungal infection cause a significant disease burden in NICUs worldwide, with mortality rates recorded as high as 44%.1 The most common fungi causing invasive infection in neonates are Candida species, which account for  up to 12% of late-onset sepsis in very low birth weight (VLBW) infants (<1500g).2 Non-specific clinical features, poor sensitivity of diagnostic tests, and late recognition mean that at the time of diagnosis invasive fungal infection is often advanced. Although neonates tend to have lower mortality than older patients, CNS disease is a frequent complication and careful  neurodevelopmental follow up is cricual.

VLBW neonates are at risk of invasive fungal infection because of their immature immune system and the invasive supportive care they receive. Other risk factors include prior exposure to broad spectrum antibiotics, indwelling central venous catheters, parenteral nutrition and corticosteroid therapy.4 More recently necrotising enterocolitis has been shown to be a risk factor5

The antifungal treatment regimens used in the United Kingdom are similar to those reported from North America.6 At present there is insufficient evidence to favour one antifungal agent over another for treating VLBW infants with invasive fungal infection.7 Currently the clinical choice of therapy may be affected by concerns about the risk of toxicity associated with the various drugs. For example, in some patients, evidence exists that renal toxicity is higher with conventional amphotericin B than with lipid complex formulations or with azole drugs. However, there are only a few observational data on the relative risks of toxicity of antifungal drugs in VLBW infants.6

Studies have shown that colonisation with Candida spp. is an important risk factor for subsequent infection.8 Prophylactic nystatin has been shown to reduce the incidence of colonisation and invasive Candida infection in this population. The Infectious Disease Society of America (IDSA) has published a consensus statement on the treatment of candidiasis.8

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Clinical Diagnosis

1. Urine positive for Candida spp.

  • Baby may be asymptomatic or show non-specific signs of sepsis. The culture may represent sample contamination. Obstructive uropathy can develop due to fungal hyphae obstructing the collecting systems in the kidneys. An ultrasound may reveal fungal balls.

2. Candidaemia (positive blood culture / isolated from long line tip)

  • Candidaemia should NEVER be considered to represent sample contamination. The neonate may show non-specific signs of sepsis – lethargy, glucose intolerance, abdominal distension, respiratory distress. There may be mucocutaneous candidiasis, an erythematous rash or fever. Thrombocytopenia often accompanies candidaemia. The white cell count however is often normal.

3. Candida Meningitis (positive CSF culture)

  • Significant risk factors include intracranial shunts or catheters. The neonate may have an altered conscious level and convulsions. Visible signs may include irritability or a tense fontanelle. Thrombocytopenia often accompanies candidal meningitis.

4. Other invasive Candida Infections

  • Other manifestations of invasive Candida include endocarditis, brain abscess, septic arthritis, endophalmitis, osteomyelitis and peritonitis

Suspected (but unproven) invasive Candida infection

  • Suspect if any risk factors are present such as VLBW baby with indwelling catheters. If an “at risk” infant is clinically septic despite 48 hours IV antibiotics AND the Blood cultures are negative and the baby has thrombocytopenia or a significant or increasing CRP then investigate and treat for fungal infection. See guideline suspected candidiasis

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Investigation

1. Urine positive for Candida spp.

  • DO NOT TREAT on the basis of a positive bag or cotton wool ball sample
  • Obtain a supra-pubic aspirate (SPA) sample, or if unobtainable 2 clean catch samples. Samples should be sent to both Microbiology (in boric acid, for microscopy and culture) and Mycology (for fungal culture only).
    • Supra pubic aspiration should be attempted only after confirming the presence of a full bladder by ultrasound.
  • If no fungi are seen on microscopy of the SPA sample and the baby is well – observe and await culture.
  • If yeasts are seen on microscopy or cultured from the SPA or both clean catch samples obtain:
    • blood culture
    • FBC
    • CRP
    • Renal USS
      And commence treatment
  • Other investigations that may be required after discussion with a senior colleague:
    • CSF
    • Cranial USS

2. Candidaemia (positive blood culture / isolated from long line tip)

  • blood culture
  • FBC
  • CRP
  • Urine culture
  • CSF
  • Repeat blood culture if still unwell after 48 hours
  • Renal USS (weekly until normal)
  • Cranial USS (weekly)
  • Plain abdominal x-ray (to look for bowel perforation)
  • Echocardiogram
  • Ophthalmology examination (endophthalmitis is a late complication)

3. Candida Meningitis (positive CSF culture)

  • blood culture
  • FBC
  • CRP
  • CSF
  • Urine culture
  • Renal USS
  • Cranial USS (to look for micro-abscesses)
  • Echocardiogram
  • Ophthalmology examination
  • Follow-up audiology assessment

4. Other invasive Candida Infections

  • Specialist microbiological and/or mycological advice should be sought.

Suspected (but unproven) invasive Candida infection

  • Repeat blood cultures (peripheral and from all central lines)
  • Urine culture (SPA)
  • CSF culture
  • Renal USS
  • Echocardiogram
  • Cranial USS

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Treatment

1. Urine positive for Candida spp.

  • Treat with systemic antifungal agent for a minimum of 14 days
  • First line treatment should be IV Ambisome (liposomal amphotericin) (see appendix) until the organism and sensitivity is identified. Treatment should be rationalised as follows:
    • Whatever Candida species is identified, Ambisome should be continued unless diagnoses of Candida Meningitis or endocarditis are considered unlikely or have been excluded by appropriate investigations.
    • If these diagnoses have been excluded the following treatments are recommended:
      • C. albicans or C. parapsilsosis: Fluconazole PO/IV
      • C. krusei: Ambisome IV
      • C. glabrata or C. tropicalis: either Fluconazole PO/IV or Ambisome IV (after discussion with microbiologist)

2. Candidaemia (positive blood culture / isolated from long line tip)

  • Remove all indwelling catheters. Replace as necessary, preferably after at least 24 hours antifungal treatment.
  • Treat with systemic antifungal agent for a minimum of 14 days after the last blood culture isolate of Candida, or line removal, whichever is later.
  • First line treatment should be IV Ambisome (see appendix) until the organism and sensitivity is identified. Treatment should be rationalised as follows:
    • Whatever Candida species is identified, Ambisome should be continued unless diagnoses of Candida Meningitis or endocarditis are considered unlikely or have been excluded by appropriate investigations.
    • If these diagnoses have been excluded the following treatments are recommended:
      • C. albicans or C. parapsilsosis: Fluconazole PO/IV
      • C. krusei: Ambisome IV
      • C. glabrata or C. tropicalis: either Fluconazole PO/IV or Ambisome IV (after discussion with microbiologist)

3. Candida Meningitis (positive CSF culture)

  • First line treatment is IV Ambisome. There is currently no evidence-base for the use of fluconazole in neonatal Candida meningitis.
  • Flucytosine (5-fluorocytosine, 5-FC) may be added where clinical response is poor or in very severe disease.
  • Continue treatment for at least four weeks after symptoms have resolved.
  • Where there is a CSF shunt or intraventricular device specialist neurosurgical and mycological advice should be sought.

4. Other invasive Candida Infections

  • Specialist microbiological and/or mycological advice should be sought.

 

Table of drug doses

Drug

Dose

Administration

Monitoring

Adverse Effects

Fluconazole 
Treatment (PO/IV)(12,14)

<2 weeks
12mg/kg/dose daily every 3rd day

2-4 weeks 
12mg/kg/ dose daily every 2nd day

>4 weeks
12mg/kg/
dose once daily

Discuss with pharmacist if there is renal impairment

Slow infusion over 10-30 minutes or use oral suspension. There is no need for a dose conversion.

LFTs
Potassium
FBC

Diarrhoea, skin rash.

Deranged LFTs, usually transient.

Hypokalaemia

Anaemia
Low platelets

Contraindications to Fluconazole:

  • Hypersensitivity to azole compounds.
  • Co-administration of Cisapride or terfenadine

    Interactions:
  • Fluconazole enhances plasma levels of phenytoin, theophylline, zidovudine and midazolam

    Side effects:
  • Stevens Johnson syndrome / Toxic epidermal necrolysis
  • Elevated liver enzymes (in 5 - 7%)
  • Occasional eosinophilia, anaemia, thrombocytopenia and hypokalaemia.

 

Drug

Dose

Administration

Monitoring

Adverse Effects

Ambisome (12,13,15, 16)

Initial test dose 100micrograms/kg then:

1mg/kg dose once daily, increasing by 1mg/kg/day to 3mg/kg once daily.

Slow iv infusion over 30-60 minutes

Renal function
Potassium
Magnesium
Phosphate
LFTs

Avoid other nephrotoxic drugs if possible

Acute infusion related reactions: fever, chills, vomiting, tachypnoea, GI effects.

Nephrotoxicity
Hypokalaemia
Hypomagnesaemia
Anaemia

Flucytosine(15)

<7 days 
25mg/kg/dose every 6 hours

>7 days 
25-50mg/kg/
dose every 6 hours

iv infusion over 20-40 minutes through a 15 micron filter.

Measure serum level at 48-72 hours:
Trough >20mg/l
Peak (measure 30 minutes after end of infusion): <70mg/l

Monitor FBC and LFT before and during treatment

Vomiting, diarrhoea, rash, elevated LFT, leucopenia, thrombocytopenia, agranulocytosis, hypoglycaemia, hypokalaemia.

Side effects more likely if serum level >100mg/l

For interactions and side effects of ambisome and flucytosine see BNF 2009

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Provenance

Record: 305
Objective:

Aims
• To improve the diagnosis, investigation, management and prevention of Invasive candidiasis in neonates

Objectives
• To provide evidence-based recommendations for appropriate investigation of Invasive candidiasis in neonates
• To provide evidence-based recommendations for appropriate antimicrobial therapy of Invasive candidiasis in neonates
• To recommend appropriate dose, route of administration and duration of antimicrobial agents.
• To advise in the event of antimicrobial allergy.
• To set out criteria for referral for surgery or specialist input.

Clinical condition:

Candida Infections in neonates

Target patient group: Neonates
Target professional group(s): Secondary Care Doctors
Secondary Care Nurses
Adapted from:

Evidence base

  1. Healy et al. Fluconazole Prophylaxis in Extremely Low Birth Weight Neonates Reduces Invasive Candidiasis Mortality Rates Without Emergence of Fluconazole-Resistant Candida Species. Pediatrics 2008;121;703-710
  2. Stoll et al. Late-onset sepsis in VLBW neonates: the experience of the NICHD Neonatal Research Network. Pediatrics 2002; 110(2);285-291
  3. Manzoni et al. A Multicentre, Randomized Trial of Prophylactic Fluconazole in Preterm Neonates. N Engl J med 356;24: 2483-249
  4. Kicklighter et al. Fluconazole for Prophylaxis Against Candidal Rectal Colonisation in the VLBW Infant. Paediatrics 2001;107:293-8
  5. Barton et al. Invasive candidiasis in low birth weight preterm infants: risk factors, clinical course and outcome in a prospective multicenter study of cases and their matched controls BMC Infectious Diseases 2014, 14:327
  6. L Clerihew, T L Lamagni, P Brocklehurst, and W McGuire
    Invasive fungal infection in very low birthweight infants: national prospective surveillance study. Arch. Dis. Child. Fetal Neonatal Ed 2006
  7. Clerihew L, McGuire W. Systemic antifungal drugs for invasive fungal infection in preterm infants. Cochrane Database Syst Rev 2004;1
  8. Pappas PG et al. Guidelines for the treatment of candidiasis.
  9. Makhoul et al. Review of 49 Neonates with acquired fungal sepsis: further characterization. Paediatrics 2001; 107:61-66
  10. Rex JH, Walsh, TJ, Sobel JD. Practice guidelines for the treatment of candidiasis.
  11. Karlowicz, MG et al. Should central venous catheters be removed as soon as candidaemia is detected in neonates? Pediatrics 2000;106(5) e63
  12. McGuire W, Clerihew L, Austin N. Prophylactic intravenous antifungal agents to prevent mortality and morbidity in very low birth weight infants (Cochrane review). In The Cochrane Library, issue 1, 2003. Oxford: Updated software.
  13. F Adler-Shohet, H Waskin, and J M Lieberman. Amphotericin B lipid complex for neonatal invasive candidiasis. Arch. Dis. Child. Fetal Neonatal Ed., 2001; 84: 131 - 133.
  14. N. Linder, G. Klinger, I. Shalit, I. Levy, S. Ashkenazi, G. Haski, O. Levit, and L. Sirota
    Treatment of candidaemia in premature infants: comparison of three amphotericin B preparations. J. Antimicrob. Chemother. 2003; 52(4): 663 - 667.
  15. D. Kaufman and K. D. Fairchild. Clinical Microbiology of Bacterial and Fungal Sepsis in Very-Low-Birth-Weight Infants. Clin. Microbiol. Rev.2004; 17(3): 638 - 680.
  16. H Smith and P Congdon. Neonatal systemic candidiasis. Arch. Dis. Child. 1985; 60: 365 - 369.
  17. Huttova M, Hartmanova I, Kralinsky K, et al. Candida fungemia in neonates treated with fluconazole: report of forty cases, including eight with meningitis. Pediatr Infect Dis J.1998; 17 :1012 –1015 
  18. L Clerihew, T L Lamagni, P Brocklehurst, and W McGuire. Candida parapsilosis infection in very low birthweight infants. Arch. Dis. Child. Fetal Neonatal Ed.2007; 92(2): 127 - 129. NB - This last article states that C. parapsilosis is best treated with Ambisome but this doesn’t conform to previous guidelines??

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Approved By

Improving Antimicrobial Prescribing Group

Document history

LHP version 1.0

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