management of systemic fungal infection in newborn
TRANSCRIPT
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