Management of systemic fungal infection in newborn

D. K. BHAGWANI

1. Introduction1. premature infants are at risk of invasive fungal infections -their relative

immunodeficiency.

2. The overall incidence of fungal septicemia on neonatal units is increasing because of both increased survival of VLBW neonates and use of broad spectrum antibiotics.

3. Invasive fungal infections are caused by Candida species

4.C albicans is responsible for most neonatal infections (up to 80% ), whereas C parapsilosis and C tropicalis account for 14% and 6% of infections respectively.

4. Colonisation of healthcare workers with fungus (predominantly C parapsilosis ) is common and can be as high as 30%. This organism is usually responsible for NICU outbreaks.

2. Candida colonisation1. fungal colonisation is seen in 10% of VLBW infants by the first week of life and this can increase more than 50%by the 4th week of life.

2. Intial site of colonisation is usually gastrointestinal tract.

3.Colonisation with fungal organisms is an independent risk factor for subsequent invasive fungal infection, particularly in VLBW infants and the rate of progression to invasive candidiasis can vary from 7 to 24%.

4.. Colonisation is the isolation of candida from high risk sites ( catheter urine, ETT).

3. Candidiasis/candidaemia: 1. Infection/ isolation of candida species in the blood.

2.Invasive candidiasis is an important cause of neonatal sepsis in VLBW infants accounting for upto 12% of late onset infection and carries an overall mortality of up to 30%.

2. Candida species is the 3rd mo0st frequent organism isolated (after CONS and Staph. aureus).

4. Invasive/ Disseminated candidiasis 1. Isolation of candida from other normally sterile body fluids or a

persistent infection after removal of catheter.

2. Candida is capable of invading all vital organs and following candidaemia, end organ dissemination is more likely with persistent candidaemia of more than 7 days.

3. Disseminated candidiasis involving the CNS has a mortality rate of 30% and survivors have a high incidence (up to 50%) of neurodevelopmental including cerebral palsy, hearing and visual problems.

4. Usual CNS involment includes Meningitis (15%), and Ventriculitis (4%).

5. Candida also results in other end organ damage such as endopthalmitis (3%), endocarditis (4%) and renal fungal balls which may calcify (5%)

5. Risk factors and transmission: Transmission of cabndida may be vertical ( from maternal

to vaginal infection/colonisation) or horizontal.

1. Low birth weight (<1500g) and low gestational age (<28 weeks)

2. use of broad spectrum antibiotics and/or multiple antibiotics

3.central venous catheters 4.parentral nutrition, being NBM 5. H2 receptor blockers 6. fungal colonisation in VLBW infants.

Risk factors for IFI in neonatal period

Tezer H, et al. Expert Opin Pharmacother 2012; 13(2): 193-205.

Low gestational age or birth

weight

Invasive devices &

procedures (e.g.,

central venous

catheters, mechanical ventilation)

Prolonged use of

parenteral nutrition

GI pathology including congenital

anomalies & necrotizing enterocoliti

s

Treatment with

corticosteroids

Delayed enteral feeding

Treatment with broad-spectrum antibiotics (particularl

y cephalospor

ins)

Neonatal candidiasis 3rd most common cause of late-onset sepsis in NICU

(high risk)

Bimodal frequency: early-onset (within 3 days of birth) & late-onset (7 – 60 days & later)

Median gestational age: 27.5 weeks

Mortality in neonatal patients: 25 – 60%

Castagnola E, et al. Drugs 2009; 69 (1): 45 -50.

6. Clinical manifestations:1. The clinical picture of systemic fungal infection in

neonates is indistinguishable from bacterial sepsis.

2.Often signs and symptoms are generalised such as apnoea, worsening cardio respiratory function, abnormal renal function and/or seizures.

3.. Candidiasis can also present with GIT symptoms similar to NEC, where there may be paucity of classic radiological signs of NEC.

7. DIAGNOSIS:. 1. Isoaltion of candida from blood or other sterile body

fluids is diagnostic.

. 2. Always consider candida in the differential diagnosis of neonatal sepsis. Particularly late onset sepsis.

8. Management: 1. When a blood culture is positive for candida.

2.important investigations include: urine MC+S, LP, renal and cranial USS and ophthalmological examination (as candida may worsen ROP and causes endopthalmitis).

3. Fungal endocarditis may occur even with only one positive blood culture, so consider an Echocardiogram if there is clinical suspicion of endocarditis.

4. Consider taking out the long line as prompt removal of central catheters is associated with improved short and long term outcomes.

4. Commencing antifungal thetrapy has to be a Neonatal consultant decision often involving the microbiologists.

9. Prophylaxis 1. Oral Nystatin suspension 0.5ml OD is given to infants <27

weeks gestation and/or <750gms from birth until removal of central venous catheters and whilst on broad spectrum antibiotics.

2.This is shown to reduce both colonisation of gastrointestinal tract and the rate of invasive candidiasis.

3. Fluconazole prophylaxis is effective in reducing the rate of colonisation and progression to systemic infection in neonatal units with a high rate of fungal infection (>10%).

4. Oral nystatin used in unit the incidence of systemic fungal infection is very low (1%), hence Fluconazole prophylaxis is currently not indicated (the NNT to prevent one case on the unit is around 200).

Antifungals used in neonatal period & susceptibility of fungus

Tezer H, et al. Expert Opin Pharmacother 2012; 13(2): 193-205.

• Irreversibly binds to ergosterol component of fungal cell membrane

Step 1

Fungicidal activity is believed to be caused by leakage of essential nutrients from the fungal cell

Mechanism of Action of Amphotericin B

LAmB: MOA Step 1 and 2

LAmB: MOA Step 3 and 4

AmB Lipid Complex

AmB Colloid Dispersion

AmB Liposomes

Occurred when AmB conc increased > 3 mol %

Dimyristoyl phosphatidylcholine DMPCDimyristoyl phosphatidylglycerol DMPGRatio 7:3Size: 1600-11,000 nmRibbon-like structureABELCET, 1981

Complexed with non-PL carrier1:1 molar ratio of AmB plus cholesteryl sulfate

2 molecules of AmB and 2 molecules of CS forming a tetramer that has hydrophilic and hydrophobic portion

Aggregates into disc-like structureNot a liposomeSize: 120-140 nmAMPHOCIL, 1995

True liposomal structureSterol component and PL component

Hydrogenated soy PCCholesterolDMPGRatio 10:5:4Size: < 80 nmAMBISOME, 1997

Lipid-based deliveries of amphotericin B

Increased daily dosage up to 10-fold

Mean duration of Rx with LAmB is shorter than Amb

but has similar efficacy

High tissue concentrations in lungs, liver & spleen

Higher dose administered with LAmB than AmB, but has

1. infusion related side effects

2. renal toxicity & hepatotoxicity

Extent of tissue distribution

may be animportant

determinant of treatment outcomes

Jeon GW, et al. Yonsei Med J, 2007; 48 (4): 621-626

Advantages of LAmB over Conventional AmB

Nephrotoxicity with Amphotericin B Nephrotoxicity common ARF rates: 49%-65%

Wingard study Serum creatinine x 2 in 53% cases Represents ↓ renal function by 70% 15% patients reqd dialysis

Pathophysiology Glomerular vasoconstriction Direct damage to tubular cells

How Soon? 45 min after infusion

How does amphotericin B cause nephrotoxicity?

Direct damage of distal tubular membranes leading to wasting of Na+, K+ and Mg++

Tubular-glomerular feedback: Further constriction of arterioles

Constriction of afferent arterioles leading to

decreased glomerular filtration

LAMBIN 10: ADR Transfusion Rxn, chills/rigors, abdominal pain, asthenia, back/chest pain

Fever, phlebitis, sepsis, hypertension, hypotension, tachycardia, hyperventilation, diarrhea, gastrointestinal hemorrhage, nausea, vomiting

↑ Alk P, ↑ALT, ↑ AST, bilirubinemia, ↑ BUN, ↑ creatinine, edema

Hyperglycemia, hypernatremia, hypervolemia, hypocalcemia, hypokalemia, hypomagnesemia

Peripheral edema, anxiety, confusion, headache, insomnia, increased cough, dyspnea, epistaxis, hypoxia, lung disorder, rhinitis, pruritus, rash, sweating, hematuria, pleural effusion

10. Treatment

Dose Mode of action

Monitor

LIPOSOMAL AMPHOTERCIN1st line in systemic fungal infection

3mg/kg/day IVStart at 1mg and increase dose every 24h.Doses upto 5mg/kg have been used.

Fungicidal- binds to ergosterol im\n fungal cell membrane and cause leakage of cations- cell death

Renal function serum K and Mg

FLUCONAZOLE1st Line in fungal UTI,2nd line in systemic fungal infections

12mg/kg/day IV/PO

Fungistatic- inhibits fungal cytochrome P-450 – Enzyme inducerUrinary concentration 10* that in plasma.

Transaminases weekly

Alternatives: caspofungin 2mg/kg/d is fungicidal, poor CSF penetrance.

Flucytosine can be used as adjunct to Amphotercin, only available PO.

DURATION OF ANTIFUNGAL THERAPYCondition Duration of treatment

Catheter- related infection Minimum of 7days after removal of catheter

Fungaemia 14-21 days after clinical improvement and negative blood culture

Endocarditis Minimum of 6 weeks, surgery often require for cure

Endopthalmitis 6- 12 weeks after vitrectomy

Meningitis Minimum of 4 weeks after resolution of signs and sympotms

Simple UTI 2 weeks

SUMMARY

SPECIAL CARE FOR YOUR LITTLE ONE